Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[C:28]([Cl:30])[CH:29]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+].O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:31]([C:26]2[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=2)(=[O:33])=[O:32])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc(CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.5 %

Procedure:
4-(4-Benzyl-piperazin-1-yl)-1H-indole (274 mg, 0.94 mmole) and 50 mg tetra-n-butylammonium hydrogen sulfate was stirred in a mixture of 10 mL toluene and 5 mL 4 N sodium hydroxide. Solid 3,5-dichlorobenzenesulfonyl chloride (246 mg, 1.0 mmole) was added in one portion. The reaction mixture was stirred at room temperature for 6 hours, then it was diluted with 20 mL water and extracted with 25 mL ethyl acetate. The organic phase was washed with 10 mL saturated sodium chloride solution, dried (magnesium sulfate) and concentrated. Recrystallization from dichloromethane provided 473 mg of 4-(4-benzyl-piperazin-1-yl)-1-(3,5-dichloro-benzenesulfonyl)-1H-indole, m.p. 201-203° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:19]1[CH:20]=[C:21]([N:25]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:38]([O-])(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:12]1([C:11]([C:19]2[CH:20]=[C:21]([N:25]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[CH2:38])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)c2ccccc2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(N(Cc2cccnc2)S(=O)(=O)CC)c1
Temperature: 25 °C

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.269 g, 0.752) in 3 mL THF at 0° C. was added KHMDS (0.5 M in toluene, 1.5 mL, 0.752 mmol). The mixture was warmed to ambient temperature for 1 h and N-(3-benzoylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.143 g, 0.376 mmol) as a solution in 3 mL THF was added via cannula. After 3 h the mixture was poured into saturated NaHCO3 solution and Extracted with EtOAc, dried over MgSO4, filtered and concentrated. The residue was chromatographed with 10:1 to 5:1 DCM/EtOAc to give the title compound as a clear oil. 1H NMR: 8.50 (dd,J=4.9, 1.5 Hz, 1H), 8.35 (d,J=2.0 Hz, 1H), 7.70 (dt,J=7.8, 2.0 Hz, 1H), 7.37-7.19 (m,9H), 7.14 (m,1H), 5.48 (d,J=1.0 Hz, 1H), 5.39 (d,J=1.0 Hz, 1H), 4.85 (s,2H), 3.09 (q,J=7.3 Hz, 2H), 1.41 (t,J=7.3 Hz, 3H). MS calcd. 378.1; MS (M+1) 379.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH:28]=[C:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]1=[O:42])(=O)=O.O>CN(C=O)C>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]2[CH:26]=[CH:25][C:24](=[O:42])[N:23]([CH2:22][CH2:21][CH2:20][S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OCCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Reactant: Oc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCSc1cccc(O)c1
Reaction time: 7 h
Yield: 81.1 %

Procedure:
To a solution of 3-hydroxythiophenol (222 mg) in DMF (15 mL) were added K2CO3 (243 mg) and 3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl methanesulfonate (700 mg) at ambient temperature and the mixture was stirred for 7 hours. Water was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford 5-(diphenylmethyl)-1-{3-[(3-hydroxyphenyl)sulfanyl]propyl}pyridin-2(1H)-one (610 mg) as a colorless oil.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[CH:1]1[N:2]=[C:3]([CH:18]=[O:19])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: CN(C)C=O
Reactant: c1ncn2c1CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc2n1CCCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (prepared as described by Lattrcll, R. et al. The J. of Antibiotics 1988, 41, 1395-1408) in THF (7 mL) at −78° C. was added a solution of n-BuLi (2.5 M in hexanes, 0.70 mL, 1.75 mmol) and the reaction stirred at −78° C. for 10 min. DMF (1.0 mL) was added to the mixture at −78° C. and the reaction warmed to room temperature and stirred for 2 h before quenching with saturated aqueous NH4Cl (5 mL). The mixture was diluted with EtOAc (30 mL) and brine and the organic phase washed with brine (1×30 mL), dried (Na2SO4) and concentrated in vacuo. The resultant brown oil (191 mg) was purified by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) to afford the desired aldehyde (105 mg, 40%) as an orange oil. 1H NMR (CDCl3) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J=6 Hz), 4.39 (t, 2H, J=6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).
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.[CH2:32]1C2C(=CC=CC=2)CC[CH:33]1C(O)=O.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([N:11]([CH2:10][CH:9]2[CH2:33][CH2:32][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH2:8]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)[CH2:30][CH2:29]1
Reactant: O=C(O)C1CCc2ccccc2C1
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: C[C@H]1CC[C@H](N(CC2CCc3ccccc3C2)C(=O)Nc2ncc(SCC(=O)O)s2)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 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 371 mg (19%) of the expected methyl ester, with a melting point of 84°-85° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:34]=[CH:33][C:15]([C:16]([N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:25]1[C:23]2[CH2:24][N:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:34][CH:33]=3)=[O:17])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[S:21][C:22]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of 385 mg of 2-chloro-benzoyl chloride in 6 ml of methylene chloride at 0° C. is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f]-[1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.7 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.3 g of the desired product, m.p. 116°-119° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[C:30]([C:29]1[C:24]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.6 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (10.0 g), 2-chloro-3-cyanopyridine (4.27 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.48 g) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (10.98 g, 90%) of 3-cyano-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 119-120° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29](=[O:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:34])[C:28]3[C:35]([CH3:36])=[C:24]([N:21]4[CH2:22][CH2:23][N:18]([C:15]5[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=5)[CH2:19][CH2:20]4)[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]=3[O:31][C:30]2([CH3:32])[CH3:33])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC)cc3)C(C)(C)O4)CC2)cc1
Yield: 95 %

Procedure:
Using 4-bromoanisole and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 95%. mp. 157–159° C. (hexane).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[K+].[I:16]I.C(OCC)(=O)C>CN(C=O)C>[I:16][C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: II
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A mixture of 6-(trifluoromethyl)-1H-indazole (0.5 g, 2.69 mmol), KOH (0.45 g, 8.1 mmol) and I2 (1.37 g, 5.38 mmol) in dry DMF (20 mL) was stirred for 16 hours at room temperature. Ethyl acetate (100 mL) was added and the mixture was washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was then washed with ether (2 mL) and filtered to afford 3-iodo-6-(trifluoromethyl)-1H-indazole (688 mg, crude) as a yellow solid. LCMS: (M+H)+=313.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH:26]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[CH2:27].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[C:31]1([S:28]([CH:26]=[CH:27][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)(=[O:30])=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2cnc3cc(C=CS(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Temperature: 100 °C
Yield: 49.4 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (1.00 g, 2.46 mmol), phenyl vinyl sulfone (0.852 g, 5.06 mmol), palladium(II) acetate (12 mg, 0.05 mmol), and tris(2-tolyl)phosphine (32 mg, 0.10 mmol) were added to a pressure tube. Triethylamine (1.37 mL, 9.84 mmol) and acetonitrile (5 mL) were added. The tube was flushed with nitrogen, sealed with a TEFLON plug and heated at 100° C. for 96 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was initially purified by flash column chromatography (silica gel, eluting with a gradient of 50%-100% ethyl acetate in hexanes, followed by a gradient of 2%-6% methanol in ethyl acetate). Recrystallization of the resulting solid from acetonitrile provided 0.600 g 7-(2-benzenesulfonylvinyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(Cl)c2)[C@@H](N)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of the compound (14.4 g) obtained in step 5 in toluene (120 mL) were added DPPA (16.5 g) and triethylamine (8.36 mL) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure to give crude tert-butyl (3R*,4S*)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (13.3 g, 100%) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Reactant: Brc1cccc2cc[nH]c12
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4cc[nH]c34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 7-bromo-indole. Purify the material by silica gel chromatography eluting with hexanes/ethyl acetate 4:1 to provide the title compound as a white solid. Mass spectrum (m/e): 398.25 (M*+1).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][C:2]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31](OCC2CC2)[CH:30]=1>C(OCC)(=O)C.[Pd].CCO>[C:2]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH:2]4[CH2:1][CH2:5][CH2:4][CH2:3]4)[CH:7]=3)[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:30][CH:31]=1)([CH3:6])([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(C3=CCCC3)ccc2n1Cc1cccc(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C3CCCC3)ccc2n1Cc1cccc(OC)c1
Reaction time: 16 h
Yield: 187.3 %

Procedure:
A solution of ethyl 5-(1-cyclopenten-2-yl)-3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 128, 225 mg, 0.44 mmol) in ethyl acetate (3 mL) and ETOH (3 mL) was added to a slurry of 10% palladium on charcoal (100 mg) in ethyl acetate (2 mL) and EtOH (2 mL). The reaction was placed under hydrogen (1 atm) and stirred for 16 h. The mixture was filtered through a pad of Celite using ethyl acetate to rinse. Evaporation of the filtrate gave 210 mg (93%) of the product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.37-7.53 (m, 6 H), 7.28 (dd, 1 H), 7.19 (dd, 1 H), 6.67-6.82 (m, 3 H), 5.83 (s, 3 H), 4.08 (q, 2 H), 3.75 (s, 3 H), 3.06 (p, 1 H), 1.99-2.06 (m, 2 H), 1.47-1.83 (m, 6 H), 1.40 (s, 9 H), 0.98 (t, 3 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C=O)C>[C:20]([S:22][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1)(=[O:23])[CH3:21].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CC([O-])=S
Reactant: BrCc1ccc(-[c-]2cccc2)cc1
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Solvent: CN(C)C=O
Product: CC(=O)SCc1ccc(-[c-]2cccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general procedure (Zhang et al. (1999) Tetrahedron Lett., 40: 603-606), a solution of 19 (1.5 g, 4.2 mmol) in DMF (10 mL) was added to a solution of potassium thioacetate (0.60 g, 5.0 mmol) in DMF (10 mL) and the mixture was stirred overnight at rt. The mixture was filtered and water was added to the filtrate. The filtrate was extracted with ethyl ether (3×50 mL), and the combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:1) affording a yellow solid (1.3 g, 90%): mp 79-81° C.; 1H NMR δ 2.38 (s, 3H), 4.05 (s, 5H), 4.12 (s, 2H), 4.31 (A2B2, J=1.5 Hz, 2H), 4.62 (A2B2, J=1.5 Hz, 2H), 7.21, 7.41 (AA′BB′, J=8.5 Hz, 2×2H); 13C NMR δ 31.1, 34.0, 67.2, 69.6, 70.3, 85.7, 127.0, 129.5, 135.7, 139.1, 196.1; FAB-MS obsd 350.0431, calcd exact mass 350.0428; Anal. Calcd for C19H18FeOS: C, 65.15; H, 5.18. Found: C, 64.91; H, 5.15.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19](=[O:27])[N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:30])[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:20]1[C:19](=[O:27])[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:45])=[CH:3][C:4]=3[F:30])[CH:13]=2)=[CH:21]1
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C([O-])O
Agent: Oc1cccc2[nH]nnc12
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(=O)n(CCN(C)C)c4)sc23)c(F)c1
Yield: 52.3 %

Procedure:
To a solution of compound 422 (25 mg, 0.059 mmol) in DMF (0.5 mL) was added the acid 27 (25 mg, 0.12 mmol), hydroxybenzotriazole (11 mg, 0.071 mmol), then EDC (23 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 6 hours before the addition of saturated NaHCO3 (8 mL). The mixture was then extracted with dichloromethane; the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by flash chromatography (eluent a gradient of 0 to 20% methanol in dichloromethane) to give title compound 417 as a white solid (19 mg, 53% yield). 1H NMR: (DMSO-d6) δ(ppm): 10.58 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.28 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.95 (dd, J=2.8, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.45 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 1H), 7.07-7.03 (m, 2H), 6.92-6.88 (m, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.51 (d, J=9.6 Hz, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.62 (s, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.47 (s, 6H). MS (m/z): 308.5 ([M+2H]/2), 616.1 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10].[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22]O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:9])[C:3]=1[S:2][CH3:1])([CH3:17])([CH3:16])[CH3:15]
Reactant: CSc1c(O)cccc1O
Reactant: CC(C)(C)OC(=O)NCCCCO
Product: CSc1c(O)cccc1OCCCCNC(=O)OC(C)(C)C

Procedure:
The title compound is prepared from 2-methylsulfanylbenzene-1,3-diol and 4-(Boc-amino)-1-butanol analogous to Example 1101 step A.