Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:27]=2[S:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:32][C:27]=2[S:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)SCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)SCCS5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.1 %

Procedure:
To 20 mL of a chloroform solution containing 205 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 120 mg of 2,3-dihydro-1,4-benzodithiin-6-carbaldehyde, 41 mg of acetic acid was added, and stirred at room temperature for 4.5 hours. To the reaction mixture, 216 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1] to give 195 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodithiin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[O:17])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Yield: 60 %

Procedure:
The general procedure of Referential Example 3-1) was repeated through use of 4′-fluoroacetophenone (3.0 g) and diethyl oxalate (5.9 mL), to thereby give the title compound as a solid (3.12 g, 60%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: c1ccc2c(CCn3ccnc3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (1.12 g, 5 mmol) and imidazole (0.68 g, 10 mmol) in abs. dioxane (10 ml) was stirred at 80° C. for 4 h until according to TLC educt was no longer present. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1). Yield: 507 mg (Ind-71, 48%), colourless solid
Reaction SMILES: P([O-])([O-])([O-])=O.[OH-].[Na+].[Na+].[Cl-].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)C[CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([O-:22])(=[O:21])=[O:20])=O.[Na+].[CH2:46]1[N:51](CCS(O)(=O)=O)[CH2:50][CH2:49][O:48][CH2:47]1.Cl.CC1C(C)=C(OC(CCC(OCCO)=O)=O)C(C)=C2CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)OC=12.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O.C(Cl)(Cl)Cl>[CH2:46]1[N:51]([CH2:50][CH2:49][OH:48])[CH2:13][CH2:14][N:16]([CH2:17][CH2:18][S:19]([OH:22])(=[O:20])=[O:21])[CH2:47]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)OCCO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S(=O)(O)CCN1CCN(CCO)CC1
Temperature: 80 °C

Procedure:
FaSSIF (Fasted State Simulated Intestinal Fluid) was prepared based on blank FaSSIF which is a phosphate buffer obtained by dissolving 0.696 g NaOH (BDH Laboratory Supplies, Poole, England), 7.908 g NaH2PO4.H2O (Merck, Darmstadt, Germany) and 12.37 g NaCl in 2 L of purified water (18.2 MΩ, Elga, Tex., USA). The pH was adjusted to exactly 6.5 with 1M NaOH. FaSSIF was created by adding 3.23 g sodium taurocholate (ICN Biomedicals, Eschwege, Germany) and 5.9 mL of a solution of lecithin (YDS Chemicals, Heusden, Belgium) in chloroform (100 mg·mL−1) to approximately 200 mL blank FaSSIF. This mixture was heated to 80° C. for 15 minutes to remove all chloroform, after which a clear solution was obtained. Subsequently, blank FaSSIF was added up to a volume of 11. Some experiments were performed with MES buffered FaSSIF to allow the addition of SGF (simulated gastric fluid, 0.1M HCl containing 0.2 wt. % NaCl) without a significant pH change. MES [2-(N-morpholino)-ethanesulfonic acid, Sigma-Aldrich, Steinheim, Germany] (977.3 mg), sodium taurocholate (179.1 mg) and lecithin solution (655.6 μl) were added to prepare 100 ml of MES-FaSSIF according to the same protocol as mentioned before. As receiver medium for the Caco-2 transport experiments, 0.2 wt. % TPGS (D-α-tocopherol polyethylene glycol 1000 succinate, Eastman, Anglesey, England) in transport medium (TM) [HBSS (Hanks' Balanced Salt Solution) supplemented with glucose (to obtain a final concentration of 25 mM, Sigma-Aldrich, Steinheim, Germany) and Hepes-buffer (10 mM, pH 7.4, N-2-hydroxyethyl-piperazine-N′-2-ethanesulfonic acid, Lonza, Verviers, Belgium)] was used. To maintain sink conditions, TPGS was included in the medium added to the basolateral side of the Caco-2 cell monolayer.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16](=O)[CH2:17][CH3:18]>>[CH2:17]([C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[S:7][CH:15]=1)[CH3:18]
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Reactant: CCC(=O)CBr
Product: CCc1csc(-c2ccc(C)cc2[N+](=O)[O-])n1
Yield: 91 %

Procedure:
The procedure described in Example 15-1, was followed but 4-methyl-2-nitro-thiobenzamide (56) was used instead of 4-trifluoromethyl-2-nitro-thiobenzamide, and 1-bromo-2-butanone was used instead of 1-bromo-3-methyl-butan-2-one, which gave the title compound (90 mg, 91%). LC/MS: (Method I): tR=1.55 min, >90%, m/z (ESI+)=249 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[S:7])([O-:3])=[O:2].Br[CH2:18][C:19](=O)[CH:20]([CH3:22])[CH3:21]>O1CCOCC1>[CH:20]([C:19]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[S:7][CH:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)CBr
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CC(C)c1csc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])n1
Temperature: 100 °C
Yield: 94.8 %

Procedure:
2-Nitro-4-trifluoromethyl-thiobenzamide (55), (100 mg, 0.4 mmol) was dissolved in dioxan (4 ml) in a 10 ml test tube and to this solution was added 1-bromo-3-methyl-butan-2-one (52) (72.6 mg, 0.44 mmol). A stirrbar was added and the tube was sealed and heated to 100° C. over night. After cooling to ambient temperature, the vessel was de-capped, the solvent removed in vacuo and the residue partitioned between DCM and 10% aqueous NaHCO3 solution. The organic phase was separated and washed with additional 10% aqueous NaHCO3 solution and brine. The organic phase was filtered through a hydrophobic frit and the solvent removed in vacuo which gave the target compound (120 mg, 90%). LC/MS: (Method I): tR=2.26 min, >90%, m/z (ESI)=317 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH3:17])=[CH:4][CH:3]=1.P(=O)(O)(O)O.N>O>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][C@H:7]3[N:8]([CH3:17])[CH2:9][CH2:10][C@@:11]4([C:4]=2[CH:3]=1)[C@H:16]3[CH2:15][CH2:14][CH2:13][CH2:12]4
Reactant: Cc1ccc(CC2C3=C(CCCC3)CCN2C)cc1
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C)CC3
Temperature: 135 °C
Yield: 27.5 %

Procedure:
(+)-1-p-methylbenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (26.5 g) was added to 85% phosphoric acid (130 ml) and the mixture was heated to 130-140° C. for 72 h. After the reaction was complete, the reaction mixture was poured into ice-water and the solution was made strongly alkaline by the addition of conc. ammonia solution (about 300 ml) and diluted with water (500 ml). The solution was then extracted with ether (500 ml×2). The ether layers were combined and washed with water (200 ml), and dried (K2CO3), filtered and evaporated to yield an oil. The oil was immediately vacuum-distilled to produce a faint yellow oil (10 g; bp 130-136° C./0.3 mm Hg) which was crystallized on standing. Recrystallization from acetone (˜10 ml) provided white prisms ((7.3 g) of (+)-3-methyl-17-methyl-morphinan; MS(ESI+): m/z 256 (M+1). This procedure is similar to the procedure in U.S. Pat. No. 3,786,054, incorporated by reference herein in its entirety.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([O:39]C)=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCOCC3)Cc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCOCC3)Cc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-35 (50 mg) lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (1 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 35 mg (76%); MS APCI+ve 556 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=O)=[O:9])=[CH:4][CH:3]=1.S>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)C(=O)c2ccc(N)cc2)cc1
Agent: S
Solvent: c1ccncc1
Product: Nc1ccc(CC(=O)c2ccc(N)cc2)cc1

Procedure:
In a two-neck round bottom flask were taken t-Boc-protected 4,4′-diaminobenzil, 2 (17.5 g, 40 mmol) and 200 mL of pyridine. Hydrogen sulfide gas was bubbled through a septum and the outlet of the reaction vessel was connected to a trap containing aqueous sodium hydroxide solution (10%) to quench the unreacted H2S gas. As the reaction progressed, the solution changes from pale yellow to deep red in color and a separation of yellow solid (sulfur) was observed. As the Rf values of both starting material and product were very similar, it was difficult to follow the reaction progress by TLC. Monitoring the reaction by 1H NMR indicated that the reaction was complete after 8 h of H2S-bubbling. After removing the excess pyridine under reduced pressure, the residue was poured into dilute hydrochloric acid (5%) and the resulting off-white solid was filtered. Further washing with water, drying under vacuum, and then purification by column chromatography (1:5 mixtures of ethyl acetate and hexane) afforded the product as white fluffy solid. Yield: 16 g (94%). Mp. 203° C. 1H NMR (acetone-d6, 400 MHz): 1.49 (s, 9H), 1.46 (s, 9H), 4.23 (s, 2H), 7.21 (m, 2H), 7.48 (m, 2H), 7.66 (m, 2H), 8.02 (m, 2H), 8.34 (bs, 1H), 8.79 (bs, 1H). 13C NMR (acetone-d6, 100 MHz): 196.6, 153.7, 153.4, 145.1, 139.1, 131.7, 130.7, 130.6, 130.2, 119.1, 118.1, 80.7, 79.8, 44.9, 28.5, 28.4. FT-IR (cm−1): ν 3371, 2977, 1705, 1682, 1605, 1525, 1502, 1409, 1392, 1368, 1319, 1235, 1121, 1155, 1057, 996, 904, 826, 772. HRMS-FAB: m/z M+ calcd 426.2155. found 426.2136.
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][C:19]([CH3:37])([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:20]([OH:22])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:37])[C:20]([NH:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[O:22])=[CH:29][CH:28]=2)=[N:31][CH:32]=1
Reactant: CC(Cc1ccc(-c2ccc(F)cn2)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)CC(O)CNC(=O)C(C)(Cc1ccc(-c2ccc(F)cn2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (186 mg, 1.84 mmol) was added to an ambient temperature solution of 2-{[(benzyloxy)carbonyl]amino}-3-[4-(5-fluoropyridin-2-yl)phenyl]-2-methylpropanoic acid (150 mg, 0.37 mmol), 1-amino-4,4-dimethylhexan-2-ol (214 mg, 1.48 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol), and 1-hydroxybenzotriazole (67 mg, 0.44 mmol) in methylene chloride (5 mL). After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 40-80% ethyl acetate/hexane afforded benzyl {1-[4-(5-fluoropyridin-2-yl)benzyl]-2-[(2-hydroxy-4,4-dimethylhexyl)amino]-1-methyl-2-oxoethyl}carbamate.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28])=[O:26])=[CH:22][C:21]=3[CH:33]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:34].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]([N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28])=[O:26])=[CH:22][C:21]=2[CH:33]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:35])[C:2]([CH3:36])([CH3:37])[CH3:1])=[C:7]([CH3:34])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1
Yield: 92 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carbonyl)-methyl-amino]-acetic acid (130 mg, 0.256 mmol) in THF (2.0 mL) are reacted with NaBH4 (19 mg, 0.513 mmol) analogous to Example 8 to yield title compound (120 mg, 92%). MS (ES) m/e: 508.3 (M−1), 510.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:23].CCN(CC)CC>CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[C:17]([O:19][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:23])=[O:18]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 55 °C

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid (1.61 g, 6.11 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (2.55 g, 9.17 mmol) in MeCN (25 mL) was added Et3N (1.27 mL, 9.17 mmol). The solution was heated to 55° C. and stirred o/n. The solution was cooled to rt, diluted with EtOAc, sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was taken onto the next step crude.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[OH:45][CH2:46][C@H:47]1[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[CH2:57][CH2:58][C:59]([CH3:62])([OH:61])[CH3:60])[C@H:49]([CH3:63])[NH:48]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:48]1[C@@H:47]([CH2:46][OH:45])[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[CH2:57][CH2:58][C:59]([OH:61])([CH3:60])[CH3:62])[C@@H:49]1[CH3:63])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.9 %

Procedure:
Dissolve 2-(2-chlorophenyl)acetic acid (96.8 mg, 0.56 mmol) and O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol) in dichloromethane (2 mL). Add diisopropylethylamine (183 μL, 1.05 mmol). Stir at ambient temperature for 20 min. Add this reaction mixture to a solution of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (92 mg, 0.35 mol) in dichloromethane (0.4 mL). Rinse with dichloromethane (1 mL) and stir at ambient temperature for 3.5 hours. Dilute the reaction mixture with water and stir. Extract with dichloromethane and dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-60%) to give a residue. Purify the residue by silica gel chromatography, eluting with 10% (2N ammonia in methanol): dichloromethane to give the title compound as a white foam (78 mg, 0.19 mmol). MS (m/z): 416.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:33]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:13]([C:15]2[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=2)[N:14]=1)=[O:8].C(Cl)(Cl)Cl.[NH:39]1[CH2:49][CH2:48][CH:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:41][CH2:40]1>C1COCC1>[CH2:46]([O:45][C:43]([CH:42]1[CH2:48][CH2:49][N:39]([C:3]2[C:2]([Cl:1])=[CH:33][C:6]([C:7](=[O:8])[NH:9][C:10]3[S:11][C:12]([N:21]4[CH2:26][CH2:25][N:24]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:22]4)=[C:13]([C:15]4[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=4)[N:14]=3)=[CH:5][N:4]=2)[CH2:40][CH2:41]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(N4CCN(C5CCCCC5)CC4)s3)cc2Cl)CC1
Reaction time: 5 h

Procedure:
To a solution of 750 mg of the compound of Example 5 in 10 ml of THF, 2.1 ml of ethyl isonipecotate was added at room temperature, the temperature was elevated to 50° C., and the mixture was stirred for 5 hours. To the reaction solution, chloroform was added, and the organic layer was washed with saturated aqueous NaHCO3 and brine and dried over sodium sulfate. After the evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-MeOH=200:1˜100:1) to obtain 881 mg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19]C)=O)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH3:21]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:21])=[O:19])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(N)cc3)nc12
Reactant: N
Product: NC(=O)c1cccc2[nH]c(-c3ccc(N)cc3)nc12

Procedure:
Following standard procedure C, the acetate salt of methyl 2-(4′-aminophenyl)-1-H-benzimidazole-4-carboxylate (113 mg, 0.346 mmol) was treated with liquid ammonia under pressure for 24 hours. The pure title compound was isolated with column chromatography of the crude material using dichloromethane/methanol 90:10 (21.4 mg, 25%) mp 237-240° C.; δH 5.90 (2H, s, NH2), 6.79-6.83 (2H, d, J=8.3), 7.31-7.39 (1H, t), 7.71-7.75 (1H, d), 7.84 (1H, s, NH), 7.88-7.92 (1H, d), 8.00-8.04 (2H, d, J=8.3), 9.5-9.6 (1H, br s, NH), 13.0 (1H, br s, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=O.C([O+](CC)CC)C.Cl.[F:21][C:22]1[CH:23]=[C:24]([C:28]2([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=3)[CH:36]3[CH:32]([CH2:33][NH:34][CH2:35]3)[C:31](=[O:37])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[F:44][C:40]1[CH:39]=[C:38]([C:28]2([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)[CH:36]3[CH:32]([CH2:33][N:34]([C:10](=[NH:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:35]3)[C:31](=[O:37])[CH2:30][CH2:29]2)[CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccccc1CC(N)=O
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Agent: CC[O+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=N)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.6 %

Procedure:
A suspension of (2-methoxyphenyl)acetamide (0.9 g) in dry dichloromethane (3 cc) is treated with triethyloxonium tetrafluoborate (1.14 g) and the solution obtained is stirred for 20 hours at 25° C. After cooling to 0° C., a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.5 g) and triethylamine (1.4 cc) in dichloromethane (9 cc) is added to the reaction mixture. The reaction mixture is stirred for 30 minutes at 25° C., then refluxed for 5 hours and finally stirred for a further 16 hours at 25° C. Saturated potassium carbonate solution (50 cc) is added, the mixture is stirred and filtered and the organic phase is washed with water (2×50 cc). After drying over magnesium sulphate and filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on an alumina column (diameter 2.6 cm, height 24 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume) and collecting 15 cc fractions. Fractions 7 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolone (0.54 g) in the form of a pale yellow meringue.