Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl>O.CC(N(C)C)=O>[NH2:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:13]2[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)cc(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A flask was charged with N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitro-benzenesulfonamide (3.4 g, 7.06 mmol), prepared using procedures similar to those in Example 14, tin chloride solvate (6.4 g, 28.2 mmol), and 30 mL of DMA. A few drops of water were added and the reaction mixture was stirred at 80° C. for 3 hours, after which time, solvent was removed on a rotary evaporator, and 50 mL of water and 10 mL of Methanol were added. The slurry was filtered, and the filtrate was washed with MeOH, water, and diethyl ether (20 mL of each), resulting in 3.25 g 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.2 (br s, 1H), 8.85 (s, 1H), 7.90 (br s, 1H), 7.50-7.60 (m, 1H), 7.3-7.4 (m, 4H), 7.2 (m, 3H), 6.74 (m, 1H), 6.24 (m, 1H), 5.56 (br s, 2H), 3.76 (s, 6H). MS (EI) m/z for C22H21N5O4S: 452.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc(C(F)(F)F)c4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76-7.49,(10H, m), 4.79-4.65,(2H, m), 2.94,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.62 min, MH+ 466.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CC(N(C)C)=O.[Cu](I)I>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[CH3:10]
Reactant: NC1(C(=O)O)CC1
Reactant: Cc1cc(I)cc(C)c1Br
Agent: I[Cu]I
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC2(C(=O)O)CC2)cc(C)c1Br
Temperature: 120 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (300 mg, 0.965 mmol), 1-aminocyclopropane carboxylic acid (195 mg, 1.93 mmol), copper iodide (I) (37 mg, 0.194 mmol), and diazabicycloundecene (0.50 mL, 3.35 mmol) in dimethylacetamide (2.6 mL) was stirred at 120° C. for three hours under nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (Wakosil C18, acetonitrile-water (0.1% formic acid)) to afford 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopropane carboxylic acid (219 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([C:8]([O:10]CC)=[O:9])=[CH:5][C:4](=[O:13])[CH:3]=1.[O-]CC.[Na+].[Na].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.O>[O:13]=[C:4]1[CH:3]=[C:2]([CH:1]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1
Reactant: CCOC(=O)c1cc(=O)cc(C)o1
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(=O)cc(C=Cc2ccccc2)o1

Procedure:
A solution of this ester (3.6 g) in ethanol (100 ml) was added to a solution of sodium ethoxide prepared by dissolving sodium (0.1 g) in ethanol (100 ml). Benzaldehyde (2.45 ml) was added and the stirred mixture was heated at 80°-90° C. for an hour, cooled, diluted with water (800 ml) and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated and the solid residue was recrystallised from dimethylformamide-water to give the title product (mp 227°-228° C. with decomposition).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15](C(OCC)=O)[C:14](=[O:23])[CH:13]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH2:1]([O:8][CH:9]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][C:14](=[O:23])[CH:13]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(CCN1C(=O)C(C(=O)OCC)C(=O)C1CC(=O)OCC)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCCC(CCN1C(=O)CC(=O)C1CC(=O)OCC)OCc1ccccc1

Procedure:
The solution of 1-(3'-benzyloxy-n-octyl)-4-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-pyrrolidin-3,5-dione in ether (obtained as described above) was stirred overnight in the presence of magnesium sulphate. The mixture was filtered and the filtrate was evaporated in vacuo giving 1-(3'-benzyloxy-n-octyl)-2-(ethoxycarbonylmethyl)pyrrolidin-3,5-dione [71 g., 95% overall yield for steps b) and c)] as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-N-(2-phenylethyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2C(OC(C)(C)C)=O)=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C@H:13]12[CH2:18][C@H:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Yield: 45.9 %

Procedure:
A solution of 1,1-Dimethylethyl (1S,4S)-5-(1H-benzimidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (20 g, 58.5 mmol) in 200 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was basified by addition of sat. aqueous Na2CO3 and then extracted with DCM (4×200 mL). The DCM solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (6.5 g) as a pale yellow solid. LCMS (m/z): 243.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][NH:20][CH2:19][CH2:18]2.CCN(C(C)C)C(C)C.[O:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:19][CH2:18]2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)CCNC2
Reactant: Brc1cccc2c1CNCC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc2C1
Product: CC(C)(C)OC(=O)N1CCc2cccc(Br)c2C1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a mixture of 6-bromo-1,2,3,4-tetrahydroisoquinoline and 8-bromo-1,2,3,4-tetrahydroisoquinoline (22.1 mmol) in THF (100 mL) was added DIPEA (22.1 mmol) and BOC2O (24 mmol). The reaction mixture was allowed to stir at rt over the weekend and then concentrated. Water (5 mL) was added to the residue and the pH was adjusted to 2 by the addition of 1N H3PO4. The mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.04 g, 88%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][OH:17].[OH-].[K+]>CCCCCC.C(OCC)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:17][CH3:16]
Reactant: CO
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone from the previous step and 17 L of methanol were added to a 50 L round bottomed flask equipped with a glycol cooling jacket and a mechanical stirrer. The resulting solution was cooled to 0° C. and 87% KOH (1172 g 18.17 moles) was added in portions over approximately 1 h. The mixture exothermed to 40° C. Following the addition the mixture was allowed to stir an additional 3 h at ambient temperature. The reaction mixture was partitioned with 12 L of ethyl acetate and 12 L of H2O. The aqueous layer was extracted with ethyl acetate (2×4 L). The combined organic layers were washed with brine (2×10 L) and dried (MgSO4). The organic solution was clarified by filtration and concentrated to give a dark semi-solid. The crude material was equally divided and added to two 22 L flasks. The material was suspended in 12 L hexane/diethyl ether (2:1 ratio). The washed material was vacuum filtered on a Buchner funnel and air dried overnight to give 3,406 g (77% over 2 steps) of 4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone as a dark tan solid suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=118°-120° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[C:7]=1Cl)(=[O:5])=[O:4])[CH3:2].[CH2:17]([SH:19])[CH3:18].[OH-].[Na+].Cl.[S:23](=O)(=O)(O)O>O.C(Cl)CCl.CO>[CH2:17]([S:19][C:7]1[C:8]([Cl:15])=[C:9]([CH:13]=[CH:14][C:6]=1[S:3][CH2:1][CH3:2])[C:10]([OH:12])=[O:11])[CH3:18].[Cl:15][C:8]1[C:7]([CH2:17][CH3:18])=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[S:23]
Reactant: O=S(=O)(O)O
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Reactant: CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: CCSc1ccc(C(=O)O)c(Cl)c1SCC
Product: CCc1c(S(=O)(=O)CC)ccc(C(O)=S)c1Cl

Procedure:
A solution of the 4-ethylsulfonyl-2,3-dichlorobenzoic acid prepared in Example 3 (0.2 mole), ethyl mercaptan (0.8 mole), sodium hydroxide (1 mole) in water (300 ml) was heated at reflux for 24 hours. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid and extracted with methylene chloride. The layers were separated, and the methylene chloride layer was dried over magnesium sulfate. Evaporation of the methylene chloride in vacuo then afforded a mixture of the acids which were esterified to the methyl esters with methanol and sulfuric acid in ethylene dichloride by the procedure of Clinton and Lawkowski, J. Amer. Chem. Soc., 70, 3135 (1948). The esters were then separated via standard chromatographic techniques. Basic hydrolysis of each methyl ester then afforded the 3,4-bis-ethylthio-2-chlorobenzoic acid, m.p. 73°-75° C. and 2-chloro-4-ethylsulfonyl-3-ethylthio-benzoic acid oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:12])=[O:2].C[I:20].[I-].[CH:22](NC1C=CC=CC=1C(C1C=CC=C[N+]=1C)(C)C)=O>>[I-:20].[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[CH3:22])[CH3:12])=[O:2]
Reactant: C[n+]1ccccc1C(C)(C)c1ccccc1NC=O
Reactant: CC(Cc1ccccc1NC=O)c1ccccn1
Reactant: CI
Agent: [I-]
Product: CC(Cc1ccccc1NC=O)c1cccc[n+]1C

Procedure:
Reaction of 2-[2-(2-formamidophenyl)-1-methylethyl]pyridine (24 g., 0.1 mole) with methyl iodide (28.4 g., 0.2 mole) according to the procedure of Example 2(c), affords 29.5 g. (77%) of 2-[2-(2-formamidophenyl-1-methylethyl]-1-methylpyridinium iodide, m.p. 184° - 188° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[C:41]([Cl:42])=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(Cl)(=O)OCC(C)C.[BH4-].[Na+]>O>[Cl:42][C:41]1[C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[N:23]=[CH:22][C:21]([C:17]4[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=4)[CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:26][N:25]=3)[CH2:32][CH2:31]2)=[N:34][CH:35]=[C:36]([CH2:37][OH:38])[CH:40]=1
Reactant: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(C(=O)O)cc4Cl)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(CO)cc4Cl)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Under ice-cooling, 6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-chloronicotinic acid (303 mg), THF (9 ml), and TEA (65 mg) were mixed, and isobutyl chlorocarbonate (77 mg) was added thereto, followed by stirring at the same temperature for 1.5 hours. The reaction mixture was cooled to −78° C., and a solution of sodium borohydride (77 mg) in water (1.1 ml) was added thereto, followed by warming to 0° C. and stirring for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc, and the organic layer was washed with water and saturated brine, and dried over Na2SO4. Under reduced pressure, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (NH silica) to obtain tert-butyl (2-{[3-(2-{4-[3-chloro-5-(hydroxymethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (296 mg).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:19])=[C:11]1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:4].[OH-].[Na+].[ClH:27]>C(O)C.C(OCC)C>[ClH:27].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:19])=[C:11]1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1c(-n2ccnc2)n(CCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
A mixture of 1-(5-methoxycarbonylpentyl)-2-(1-imidazolyl)-3-methylindole (1.80 g) and 30 ml of 3N NaOH is stirred at room temperature for 1.3 hours. The resulting clear, yellow solution is neutralized to pH 6 with 2N HCl. The resulting suspension is extracted with ethyl acetate (2×50 ml). The organic extract is washed with a saturated NaCl solution (1×25 ml), dried (MgSO4), filtered, and concentrated in vacuo to give a cream-colored solid. The solid is dissolved in ethanol and the solution treated with 0.6 ml of 6.5N HCl in ethanol. The solution is diluted with diethyl ether and after standing for several hours the precipitate which forms is collected by filtration to give 1-(5-carboxypentyl)-2-(1-imidazolyl)-3-methylindole hydrochloride, m.p. 177.5°-180.5° decomposition.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].[Li]CCCC.[C:11]([C:15](OCC)=O)([F:14])([F:13])[F:12].B(F)(F)F.O(CC)CC.[NH2:29][NH2:30]>C1COCC1.C1C=CC=CC=1>[CH2:3]([C:4]1[NH:30][N:29]=[C:15]([C:11]([F:12])([F:13])[F:14])[CH:5]=1)[CH2:2][CH3:1]
Reactant: C#CCCC
Reactant: NN
Reactant: CCOC(=O)C(F)(F)F
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCc1cc(C(F)(F)F)n[nH]1

Procedure:
Following protocol H, 1-pentyne was treated with n-BuLi, CF3CO2Et and BF3—OEt2 in THF. Reaction with hydrazine in benzene under similar reaction conditions yielded title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[Br:8][CH:9]([CH2:11][CH3:12])[CH3:10]>C(#N)C>[Br-:8].[CH2:10]([N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][CH2:11][CH3:12]
Reactant: CN1CCCC1=O
Reactant: CCC(C)Br
Solvent: CC#N
Product: CCCC[N+]1(C)CCCC1
Product: [Br-]
Temperature: 65 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
About 200 mL of acetonitrile (manufactured by Junsei Co., Ltd. in Japan) was mixed with about 52.7 mL (0.5 mol) of methylpyrrolidone (manufactured by Fluka Co., Ltd.) under a nitrogen atmosphere to form a liquid mixture. Subsequently, about 58.6 mL (0.55 mol) of 2-bromobutane (manufactured by Aldrich Co., Ltd.) was added into the liquid mixture drop by drop to form a mixed solution. Subsequently, the mixed solution was stirred at about 65° C. for about 48 hours under a nitrogen atmosphere, and was then stored at about 4° C. for about 12 hours to form crystals. After a supernatant was removed from the mixed solution, the crystals were dried at a temperature of about 35° C. and a pressure of about 0.2 atm for about 12 hours using a vacuum evaporator to remove a solvent therefrom. Subsequently, in order to remove impurities, the dried crystals were dissolved in about 100 mL of acetone, and were then stirred at a temperature of about 25° C. and a pressure of about 1 atm for about 30 minutes to form a solution. The solution was left at 4° C. for about 12 hours to form crystals again. After a supernatant was removed from the solution, the crystals were dried at a temperature of about 35° C. and a pressure of about 0.2 atm for about 12 hours using a vacuum evaporator. These processes were repeatedly conducted three times to obtain N-butyl-N-methylpyrrolidinium bromide at a yield of about 60%.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])[CH3:4].[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][C@@H:15]([CH3:1])[C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29])[CH3:4]
Reactant: [Li]C
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@@H](C)[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reaction time: 0.5 h

Procedure:
A solution of methyllithium in ether (c. 2M 4 ml.) was added to a stirred slurry of cuprous iodide (630 mg.) in dry ether (60 ml.) under dry nitrogen until the initially formed yellow precipitate redissolved. A solution of 2β-ethoxy- 3α-hydroxy-5α-pregn-16-ene11,20-dione (420 mg.) in dry tetrahydrofuran (35 ml.) was added to the stirred solution at 0° and stirring was continued, at 0°, for 30 minutes. The mixture was then poured into saturated ammonium chloride solution (150 ml.), more ether (150 ml.) was added, the organic layer separated, washed with saturated ammonium chloride solution (150 ml.) and water (150 ml.) and dried (Na2 SO4). The solution was then evaporated. The residue was purified by preparative TLC (CHCl3 × 4). The least polar component was recrystallised from acetone/petrol to give title compound (130 mg.) as white needles; m.p. 178°-179°; [α]D + 112° (c 0.3).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C(N(C(C)C)CC)(C)C.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(Br)c(F)c1
Reaction time: 12 h

Procedure:
A stirred solution of 4-bromo-3-fluoro-aniline (120 g, 0.63 mol) and diisopropylethylamine (162 g, 1.26 mol) in acetonitrile (1.0 L) was heated to 60° C. and ethyl bromoacetate (105 g, 0.63 mol) was added dropwise within 2 h. The reaction mixture was stirred at this temperature for 12 h and was then evaporated to dryness. Water was added to the residue and the solid was filtered. Crystallization from petroleum ether and ethyl acetate (5:1) provided the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1
Reactant: COC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)O)cc3)c(C)c2c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of methyl 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}benzoate (1.01 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (915 mg, 94%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:7](N(OC)C)=[O:8])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH3:22])[CH:13]=[C:14]([S:16]([F:21])([F:17])([F:18])([F:19])[F:20])[CH:15]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Ethoxy-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (2.6 g) was dissolved in THF (60 ml). After cooling to 0° C., methylmagnesium bromide (6.46 ml, 3 M in ether) was added dropwise. Thereafter, the cooling bath was removed and stirring was continued at RT. After 1 h, the mixture was acidified with 1N hydrochloric acid, admixed with water and extracted by shaking twice with EA. The EA phases were dried over magnesium sulfate, filtered and concentrated. 2.25 g of the title compound were obtained.