Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34]([NH:36][CH2:37][C:38]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:39]=2[C:40]([O:42]CC)=[O:41])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([C:34]([NH:36][CH2:37][C:38]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:39]=2[C:40]([OH:42])=[O:41])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)NCc2ccc(F)cc2C(=O)O)c(OCc2ccccc2)c2ncccc12

Procedure:
Ethyl 2-((8-(benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxamido)methyl)-5-fluorobenzoate (Example 1.3; 0.64 g; 0.96 mmol) was dissolved in ethanol (4 ml). A solution of 1N NaOH (1.5 ml) was added at room temperature. After completion of the reaction, HCl 1 N was added until pH=2-3 was reached. The solvent was evaporated under pressure. The residue was taken-up in EtOAc and washed with H2O and brine. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Yield: 0.592 g (96%; used in next reaction step, without further purification).
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[OH:1]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c([N+](=O)[O-])cc2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])c(O)c(Br)c2CC1
Yield: 80.7 %

Procedure:
Bromination of 1,1-dimethylethyl 7-hydroxy-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (71 mg) was performed with NBS (41 mg) in DCM (2.2 ml) and SiO2 (426 mg) at −15° C. under nitrogen. After 15 minutes SiO2 was filtered off and the solvent was evaporated under reduced pressure. The crude was purified on silica gel (ethyl acetate/petroleum ether, 1/9) obtaining the title compound as a yellow solid (72 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]4[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]5[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC(=O)O)nc2C)c(=O)n4C)cn1
Temperature: 105 °C
Reaction time: 1.25 h

Procedure:
A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.1b, 161 mg, 0.387 mmol), 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 77 mg, 0.503 mmol), and PdCl2(PPh3)2 (17 mg, 0.024 mmol) in DMF (4.0 ml) and 1 M aqueous K2CO3 (1.16 ml) was stirred under argon at 105° C. for 1.25 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together concentrated, before being lyophilized to give the title compound as a TFA-salt and white powder. (HPLC: tR 2.38 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.22 (s, 1H), 8.46 (s, 1H), 8.23-8.14 (m, 3H), 7.87-7.79 (m, 1H), 7.74-7.68 (m, 1H), 6.94-6.88 (m, 1H), 5.15-4.98 (m, 2H), 3.89 (s, 3H), 3.60 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-methylpyrrolidine (74.8 mg, 0.88 mmol, 2.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv), and N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was t quenched by the addition of water and the resulting solution was extracted with 5×20 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:100). This resulted in 110.3 mg (72%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20](OC)=[O:21])=[C:15](B(O)O)[CH:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:13]1[CH:12]=[C:11]([F:10])[CH:16]=[CH:15][C:14]=1[C:20](=[O:21])[NH:8]2
Reactant: COC(=O)c1ccc(F)cc1B(O)O
Reactant: Nc1nccc(Cl)c1I
Product: O=c1[nH]c2nccc(Cl)c2c2cc(F)ccc12
Yield: 21.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (1.20 g, 4.72 mmol) and 5-fluoro-2-methoxycarbonylphenylboronic acid (1.03 g, 5.19 mmol) to provide 410 (250 mg, 21% yield) as a solid. LC-MS (M+H=249, obsd.=249).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH3:12])[CH3:11])[C:5]=1[Cl:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:13][C:5]1[C:6]([N:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cccc(N(C)C)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(CO)c1Cl
Temperature: 0 °C

Procedure:
2-Chloro-3-dimethylamino-benzoic acid methyl ester (0.85 g, 3.98 mmol) was placed in a round bottomed flask with tetrahydrofuran (50 mL) and cooled to 0° C. Lithium aluminum hydride (0.30 g, 7.96 mmol) was added in portions and after all the LAH was added, the reaction was allowed to warm and stir at rt for 14. The reaction was quenched by the addition of ice, then water (10 mL) was added. The organics were extracted into ethyl acetate (3×15 mL), dried (MgSO4) and concentrated down to afford (2-chloro-3-dimethylamino-phenyl)-methanol which was taken onward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8](O)[CH2:7]1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:27])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 36, 180 mg, 0.56 mmol) in methylene chloride (0.28 mL) was treated with diethylaminosulfur trifluoride (0.11 mL, 0.85 mmol). The resulting mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL). This solution was extracted with methylene chloride (3×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (71.2 mg, 39.3%) as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH2:31]>CN(C)C=O>[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH:31][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: COC(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CN1CCCC1=O
Temperature: -8 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
55 g of (2-oxo-1-pyrrolidinyl)acetic acid was dissolved in 1 l of dimethylformamide and 39.3 g of triethylamine was added thereto. After the solution was cooled to -8° C., 55.1 g of isobutyl chloroformate was added at -8° to -1° C. Then the reaction liquid was stirred at 0° to -7° C. for 10 minutes, 50.7 g of glycine methyl ester hydrochloride was added at -7° to -4° C. and stirred at -4° to -8° C. for 6 minutes. Next, 40.8 g of triethylamine was added at -8° to -3° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and triethylamine hydrochloride was filtered off. Dimethylformamide was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1200 g, chloroform-1 to 3% of methanol as the eluent) to obtain 70.5 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]glycine methyl ester as the oily substance. This was dissolved in 120 ml of methanol and 21.7 g of potassium hydroxide dissolved in 150 ml of methanol was added thereto. After reacting at room temperature for 5 hours, 40 g of acetic acid was added. The solvent was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1 kg, chloroform-5 to 20% of methanol-1% of formic acid as the eluent) and crystallized from tetrahydrofuran to obtain the titled compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21]CS([O-])(=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.[Cl-:32].[Li+]>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C@H:20]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21][Cl:32])([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: [Cl-]
Reactant: CC(C)(C)[Si](OC[C@H](CCS(=O)(=O)[O-])NS(C)(=O)=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H](CCl)NS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a 250 mL three neck flask fitted with a thermometer, condenser, stirbar, under argon was added the bis-methanesulfonyl derivative 6 (44 g, 0.091 mol) dissolved in DMF (200 mL). Lithium chloride (5.8 g, 0.136 mol) was added in one portion. The reaction mixture was heated to 80° C. with an oil bath. After 90 min the reaction was allowed to cool to room temperature and diluted with 50% ethyl acetate in hexanes (880 mL). The layers were separated and the organic layer was washed with water (2×550 mL) and brine (550 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to 35 g (90%) of the chlorosulfonamide 7 as a yellow viscous oil. HPLC analysis showed a purity of 95%. 1H NMR (300 MHz, CDCl3) δ 7.3-7.7 (m, 10H), 4.6-4.8 (m, 1H), 3.6-4.0 (m, 5H), 2.9 (s, 3H), 1.1 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][C@@H:13]1[CH3:22].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][C@@H:13]2[CH3:22])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 27, 2.5 g, 15.82 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.72 g, 15.82 mmol) in dichloromethane (200 mL) were added HOBt (2.42 g, 15.82 mmol) and N-methyl morpholine (5.2 mL, 47.46 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.43 g, 28.47 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in petroleum ether) afforded methyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 2.2 g (46%) as brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1>C(OCC)(=O)C.[Fe]>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 76 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of iron powder (90.36 g, 1.62 mol) and acetic acid (10%, 400 mL) at 80° C. was added a solution of the title compound of Step A (40 g, 0.162 mol) in ethyl acetate (200 mL) dropwise with vigorous stirring. The reaction mixture was stirred further at 76° C. for 1 h. After the reaction was complete, the hot reaction mixture was filtered through Celite® (200 g) and the filter cake was washed with ethyl acetate (1000 mL). The filtrate was washed with water (3×200 mL), sodium bicarbonate solution (5%, 3×200 mL), dried (MgSO4) and concentrated to give the crude product. The product was purified by flash chromatography to give 24.76 g of the title compound of Step B. 1H NMR (CDCl3, 400 MHz): δ7.41 (m,5H), 6.60 (m,3H), 5.04 (s,2H).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH2:6][CH:7]=[O:8])=[CH:2]1.[Br:9][C:10]1C=C(C(O)C)C=C[CH:15]=1>C(Cl)Cl.CCOCC>[Br:9][C:10]1[CH:2]=[C:3]([CH2:6][CH:7]=[O:8])[CH:4]=[CH:5][CH:15]=1
Reactant: O=CCc1ccsc1
Reactant: CC(O)c1cccc(Br)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1cccc(Br)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 3-bromophenyl-ethanol. The title compound: ES-MS: 196.9 [M-2]−; single peak at tR=3.89 min (System 2); Rf=0.66 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].FC(F)(F)C([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=1[CH2:29][CH3:30])=O.C(N(CC)CC)C>ClCCl>[CH2:29]([C:20]1[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[CH3:30]
Reactant: CCc1c(CCNC(=O)C(F)(F)F)ccc(OC)c1OC
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(CCNC(=O)CCCCC(=O)OC)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A solution of 6-chloro-6-oxohexanoic acid methyl ester (10 g) in dry dichloromethane (100 ml) was added dropwise to a stirred, cooled solution of Intermediate 2 (10.4 g) and triethylamine (5.65 g) in dry dichloromethane (100 ml). The reaction mixture was stirred for 1 h at room temperature, the solvent was removed in vacuo and the residue was purified by FCC using ether as eluent to give the title compound (15 g) as a white solid, m.p. 37°-39°.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[N+:21]([O-])=O)[CH2:5][CH2:6][CH3:7]>C(O)(C)C>[CH2:4]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[NH2:21])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCCCOc1cc(Cl)c(OCCCC)cc1N

Procedure:
To a mixture of 84 parts of reduced iron, 8 parts of ammonium chloride, 35 parts of water and 160 parts of isopropanol was gradually added 60.3 parts of 2,5-dibutoxy-4-chloronitrobenzene under reflux to reduce the nitro compound. Post-treatment was carried out in a conventional manner to obtain 53 parts of 2,5-dibutoxy-4-chloroaniline (m.p.: 43° to 44° C.).
Reaction SMILES: [C:1]([NH:4][S:5](=[O:16])([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([NH2:14])=[C:9]([Br:15])[CH:8]=1)=[O:6])(=O)[CH3:2].P(Cl)(Cl)([Cl:19])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:14][C:10]1[C:11]([Br:13])=[CH:12][C:7]([S:5]([N:4]=[C:1]([Cl:19])[CH3:2])(=[O:16])=[O:6])=[CH:8][C:9]=1[Br:15]
Reactant: CC(=O)NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(Cl)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
A mixture of 372 mg. of N1 -acetyl-3,5 dibromo sulfanilamide, 7.5 ml. of benzene, 5 ml. of phosphorous oxychloride and 230 mg. of phosphorous pentachloride is refluxed for 2 hours. The reaction mixture is cooled and concentrated in vacuo to an oil which solidified upon trituration with hexane. The solid material is filtered and washed with hexane affording N-(4-amino-3,5-dibromophenylsulfonyl) acetimidoyl chloride, which is used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:44])[C@H:33]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:44])[C@H:33]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)[C@@H](N)CSCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@@H](CSCc3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (3.00 g), S-benzyl-L-cysteine methyl ester hydrochloride (1.90 g), 1H-1,2,3-benzotriazol-1-ol (1.70 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.10 g), triethylamine (1.50 mL) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:2, volume ratio) to give the title compound (4.30 g, yield 94%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:59])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=2)=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:58]#[C:57][C:54]4[CH:55]=[CH:56][C:51]([C:48]5[NH:47][C:46]([CH:42]6[CH2:43][CH2:44][CH2:45][N:41]6[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:59])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=5)=[CH:52][CH:53]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CSC(C)(C)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5N(C(=O)C(NC(=O)OC)C(C)C)CSC5(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 23.8 %

Procedure:
(1-{4-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (83 mg, 0.167 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (66.0 mg, 0.167 mmol) and PdCl2(PPh3)2 (11.7 mg, 0.017 mmol) under an argon atmosphere. DMF (2.0 mL degassed with Argon) was added followed by triethylamine (168 mg, 1.67 mmol) and copper(I) iodide (3.2 mg, 0.017 mmol). The mixture was heated at 80° C. After 20 hours, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (32.1 mg) as a TFA salt.