Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[O:8]2.C(OC([N:37](C(OC(C)(C)C)=O)[CH2:38][C:39](O)=[O:40])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:64]>ClCCl.C(OCC)(=O)C>[ClH:64].[CH2:19]([CH:16]([O:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:39](=[O:40])[CH2:38][NH2:37])=[CH:24][CH:23]=3)[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[CH2:17][CH3:18])[CH3:20]
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(OC)c1OC
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c(OC)c1OC
Reaction time: 3 h

Procedure:
300 ml in dichloromethane of 5.66 g of 5,6-dimethoxy-7-(1-ethylpropoxy)-2-(4-hydroxyphenylthio)chromone obtained in Example 25, 2.62 g of N-t-butoxycarbonyl(Boc)glycine, and 3.08 g of 1,3-dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 3 hours. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 6.44 g of 7-(1-ethylpropoxy)-5,6-dimethoxy-2-(4-glycyloxyphenylthio)chromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:23])=[CH:3][C:4]([NH:6][C:7]1[CH:22]=[CH:21][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:23][C:2]1([CH3:1])[C:22]2[C:7](=[CH:8][C:9]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][C:10]=3[CH:21]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)N1CCc2ccc(NC(=O)C=C(C)C)cc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc3c(cc2CC1)C(C)(C)CC(=O)N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
Under an argon atmosphere, to a solution of 1.032 g of ethyl 7-[(3-methylbut-2-enoyl)amino]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 10.5 ml of dichloromethane was added 870 mg of aluminum chloride at room temperature, followed by stirring at room temperature for 3 hours. Further, 435 mg of aluminum chloride was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice-water, followed by extraction with chloroform. The combined organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: Hex-AcOEt) to obtain 431 mg of ethyl 4,4-dimethyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16])[CH3:2].P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>>[Cl:20][C:8]1[C:7]2[C:12](=[CH:13][C:4]([NH:3][CH2:1][CH3:2])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 103.3 %

Procedure:
7-Ethylamino-6-nitro-4(3H)-quinazolinone (30.0 g, 128 mmol) was suspended in phosphorus oxychloride (270 ml, 2.90 mol) and the mixture was heated at 110° C. for 2 hours under an argon gas atmosphere (to form a clear solution). After it was confirmed that the starting material disappeared, unreacted phosphorus oxychloride was removed under reduced pressure. After the residue was subjected to azeotrope with toluene, the resulting oily substances were dissolved in the necessary minimum amount of tetrahydrofuran. The tetrahydrofuran solution obtained was poured onto ice-cold water by adding a sufficient amount of sodium hydrogen carbonate, followed by extraction with ethyl acetate. The organic layer was dried (over anhydrous magnesium sulfate), and the drying agent was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (33.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[F:8].[Br:11]B(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrB(Br)Br
Reactant: OCc1ccc(F)c(Br)c1
Solvent: ClCCl
Product: Fc1ccc(CBr)cc1Br
Reaction time: 1 h

Procedure:
(3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for 1 h. The reaction was quenched with water, and the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:37][C:32]1[C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=3[CH3:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:29])=[O:28])=[C:35]([CH3:36])[O:34][N:33]=1
Reactant: Cc1noc(C)c1CN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1CN1N=C(c2c(C)n(CC(=O)O)c3ccc(F)cc23)c2ccccc2S1(=O)=O

Procedure:
{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 7.99 (d, 1H), 7.78 (t, 1H), 7.70 (t, 1H), 7.30 (d, 1H), 7.27 (dd, 1H), 6.79 (dt, 1H), 6.62 (dd, 1H), 4.71 (s, 2H), 4.39 (s, 2H), 2.23 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H) ppm. MS calculated for C24H21FN4O5S—H: 495, observed: 495.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15]([CH2:16][C@@H:17]([O:25][Si](C(C)C)(C(C)C)C(C)C)[CH2:18][CH2:19]1)=[N:14][CH2:13]3)=[O:5])[CH3:2].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(#N)C.C(Cl)Cl>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[NH:14][CH2:13]3)=[O:5])[CH3:37]
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 17β-N,N-diethylcarbamoyl-3β-triisopropylsilyloxy-6-azaandrost-5-ene (1.51 g, 2.8 mmol) in acetonitrile (100 mL) at 0° C. is treated with 48% aqueous HF (20 mL), the reaction allowed to warm to room temperature and stirred for 2 hours. The solution is then diluted with methylene chloride (200 mL), washed with H2O and saturated aqueous bicarbonate, dried over MgSO4 and concentrated to an off-white solid; yield 1.02 g crude (96%). A solution of this solid (0.48 g, 1.3 mmol) in acetone (100 mmol) is treated with Jones reagent (1 mL, 3.22M, 3.2 mmol) and warmed to room temperature. Next, isopropanol is added (10 mL), the reaction concentrated, the residue dissolved in ethyl acetate (75 mL), washed with saturated aqueous bicarbonate, dried over MgSO4 and concentrated to give 17β-N,N-diethylcarbamoyl-6-azaandrost-4-en-3-one as an off-white solid; yield: 0.22 g (46%). This material is then triturated with ether to give 172 mg pure white solid; m.p. 253°-256° C. (dec.). Anal. Calcd. for C23H36N2O2 ; C, 74.15; H, 9.74; N, 7.52. Found: C, 73.88; H, 9.77; N, 7.44.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[C:7]([C:10](=[O:21])[NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C1COCC1.O>[Cl:33][C:30]1[S:29][C:28]([C:26]2[O:25][N:24]=[C:23]([CH2:22][N:6]3[C:7]([C:10](=[O:21])[NH:11][CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[CH:8][CH:9]=[C:5]3[C:3]([OH:4])=[O:2])[CH:27]=2)=[CH:32][CH:31]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(C(C)C)CC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2ccc(C(=O)O)n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid methyl ester (example 10, 30 mg) in 5 mL of THF/water(3:1) was added LiOH (9 mg) The mixture was stirred for 2 h at 45° C. after which it was cooled to RT, acidified with TFA and concentrated. 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid was obtained after preparative HPLC(CH3CN/H2O gradient+0.05% TFA) of the residue. MS (ESI+): m/e=477 [M+H]+, chloro pattern.
Reaction SMILES: [CH2:1]([N:8]1[C:17](Cl)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([S:22]CC)[CH3:21].[Na]>>[CH2:1]([N:8]1[C:17]([S:22][CH2:20][CH3:21])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCSCC
Reactant: O=c1c2ccccc2cc(Cl)n1Cc1ccccc1
Agent: [Na]
Product: CCSc1cc2ccccc2c(=O)n1Cc1ccccc1

Procedure:
By following the same procedure as in Example 1 using 0.5 g. of 2-benzyl-3-chloro-1-oxo-1,2-dihydroisoquinoline and 0.6 g. of an aqueous solution of 20% sodium ethylsulfide, 0.37 g. of 2-benzyl-3-ethylthio-1-oxo-1,2-dihydroisoquinoline was obtained (recrystallized from cyclohexane).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1cc(C)c(C)cc1NC(=S)N1CCN(c2cccc(O)c2)CC1
Yield: 77 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: O=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[NH:3]1.CCOC(C)=O.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:40])=O>>[Cl:40][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1
Reactant: N#CC1(c2cccc(Sc3ccc4[nH]c(=O)ccc4c3)c2)CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(Sc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
5g (4.52 g, 12.5 mmol) was dissolved in phosphorus oxychloride (23 mL) and heated to 90° C. for 1 hour. The reaction was cooled to room temperature, and ice was added slowly, followed by EtOAc and NaHCO3. The aqueous layer was extracted with CH2Cl2 twice, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 5h.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Zn+])=[CH:16][CH:15]=1>C1COCC1.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>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 19 h
Yield: 88.4 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved under nitrogen in THF (100 mL) and (4-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 19 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and water. The organic layer was evaporated, dissolved in DCM and washed with NH4Cl (aq) and then dried by passage through a phase separator. The solvent was evaporated to yield a brown oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(4-fluorobenzyl)isonicotinate 7.08 g (88%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.92 (s, 3H), 4.18 (s, 2H), 6.94-7.02 (m, 2H), 7.19-7.27 (m, 2H), 7.65-7.69 (m, 2H), 8.68-8.71 (m, 1H). MS m/z 246 (M+H)+
Reaction SMILES: [F:1][C:2](=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3](OCC)=[O:4].CC(C[AlH]CC(C)C)C.O.Cl>C1COCC1>[F:1][C:2](=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][OH:4]
Reactant: CCCCCCCCCCCCCC=C(F)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC=C(F)CO
Temperature: 25 °C

Procedure:
Ethyl 2-fluorohexadec-2-enoate mixture 50 (6.83 g, 16.6 mmol, purity: 73% (GC)) was dissolved in dry THF (23 mL). At 0° C. DIBAL-H (1 M solution in heptane, 56.8 mL, 56.8 mmol, 3.4 eq.) was added dropwise. The reaction mixture was allowed to warm up to r.t. overnight and was poured into water (50 mL). 2 M hydrochloric acid (50 mL) was added and the phases were separated. The aqueous layer was extracted with diethyl ether (3×50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 27×4 cm, cyclohexane/ethyl acetate, 10:1→5.1). The diastereomeric mixture was isolated as a waxy, white solid. Yield: 2.67 g (61%), purity: 98% (GC).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].Cl>C(Cl)Cl.CO>[ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][C:4]([O:3][CH3:2])=[O:5])=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCNc1ccc(C(=O)NCCC(=O)OC)cc1N

Procedure:
The same procedure is used as in (2) with the addition of ethereal hydrochloric acid. Rf value: 0.65 (silica gel; methylene chloride/Methanol=9:1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:29]1[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=1[S:31]([NH2:34])(=[O:32])=[O:33])=[O:6]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc(Cl)ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 61.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 4-chlorobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 13 mg (62%) of the title compound.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CCCCCC.[C:20]([O:24][C:25](=[O:43])[N:26]([CH2:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][C:38](Br)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[CH:27]([CH3:29])[CH3:28])([CH3:23])([CH3:22])[CH3:21].C[Si]([N-:48][Si](C)(C)C)(C)C.[Li+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.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]>[C:20]([O:24][C:25](=[O:43])[N:26]([CH2:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][C:38]([NH2:48])=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[CH:27]([CH3:29])[CH3:28])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)N(CCN1CCCc2cc(Br)ccc21)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)N(CCN1CCCc2cc(N)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.4 %

Procedure:
A suspension of tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol in anhydrous THF (3 mL) was treated with tri-t-butylphosphine in hexane (10% wt) (0.229 mL, 0.076 mmol) and the mixture stirred for 5 minutes at room temperature. A solution of tert-butyl-2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl(isopropyl)carbamate (compound 3, 0.150 g, 0.378 mmol) in THF (7 mL) was added followed by lithium bis(trimethylsilyl)amide (1M in THF, 0.755 mL, 0.755 mmol) and the mixture heated in a sealed reaction vial at 90° C. for 3 hours. The mixture was cooled to room temperature and treated with TBAF (1M in THF, 3 mL, 3 mmol) for 30 minutes. The mixture was partitioned between water (10 mL) and ethyl acetate (100 mL), transferred to a separatory funnel and the organic layer separated. The aqueous layer (pH=10) was further extracted with ethyl acetate and the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated to give a dark brown-red residue. Purification on silica gel eluting with 2.5% 2M NH3 in methanol/97.5% dichloromethane yielded a dark brown residue, 4 (85 mg, 67.5%). 1H-NMR (DMSO-d6) δ 6.44 (d, 1H, J=8.0 Hz), 6.28 (dd, 1H, J=8.3, 2.1 Hz), 6.24-6.18 (m, 1H), 4.33-3.91 (br m+br s, 3H), 3.24-3.04 (m, 6H), 2.60-2.50 (m, 2H), 1.85-1.74 (m, 2H), 1.44 (s, 9H), 1.07 (d, 6H, J=6.8 Hz). MS (ESI+): 334 (MH+, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3CO2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[C:37]([N:40]1C2C(=CC=C(NS(C3C=CC(F)=CC=3Br)(=O)=O)C=2C(OC)=O)[C@H]2CCO[C@H]2[CH2:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][S:14]([C:8]3[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=3/[CH:6]=[CH:5]\[CH2:4][N:3]([CH2:1][CH3:2])[CH2:35][CH3:36])(=[O:15])=[O:16])[C:27]=2[C:28]([O:30][CH3:31])=[O:29])[C@H:22]2[CH2:34][CH2:33][O:32][C@H:23]2[CH2:41]1)(=[O:39])[CH3:38]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)N(C(C)=O)C[C@@H]1OCC[C@H]21
Temperature: 80 °C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl cis-(3aRS,9bRS)-5-acetyl-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 28) and heating at 80° C. for 2 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(N)=O)=[CH:11][CH:10]=1)=[O:6])[CH3:3].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:44])C>O>[CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:44])=[CH:11][CH:10]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(N)=O)cc1
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CCN)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (38.1 mMol) of 4-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]benzenepropanamide, 18.5 g (43 mMol) of I,I-bis-(trifluoroacetoxy)iodobenzene, 100 ml of acetonitrile and 20 ml of water was stirred for 8 hours at a reaction temperature of 40° C. A further 2.5 g of I,I-bis-(trifluoroacetoxy)iodobenzene were added and the mixture was again kept at 40° C. for 6 hours. The acetonitrile was distilled off in vacuo, the residue was taken up in 200 ml of water, then filtered, the filtrate was extracted once with 50 ml of diethylether and then made alkaline with sodium hydroxide. The alkaline aqueous phase was extracted three times with 100 ml of dichloromethane, the combined dichloromethane extracts were dried over sodium sulphate and freed from solvent in vacuo. The residue was purified by column chromatograph on silica gel (Macherey-Nagel, 35-70 mesh ASTM) using first of all tert.butyl-methylether and then tert.butylmethylether/methanol/conc. aqueous ammonia=9/1/0.3 (v/v/v) as eluant. 4.5 g (50% of theory) of a colourless oil were obtained.