Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.N1CCCCC1.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([NH:44][C@@H:45]3[CH2:49][N:48](C(OC(C)(C)C)=O)[CH2:47][C@H:46]3[C:57](O)=[O:58])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:57]([C@@H:46]2[CH2:47][NH:48][CH2:49][C@H:45]2[NH:44][C:42](=[O:43])[O:41][CH2:40][CH:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]3[C:39]2=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:58])[CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)[C@@H]3CNC[C@H]3NC(=O)OCC3c4ccccc4-c4ccccc43)C2)nc2ccccc21

Procedure:
(R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (138C) (3.02 g) was coupled to (3R,4S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (5 g) (138B) using the standard BOP coupling procedure from Example 138, Step C, Procedure B. The deprotection was performed according to standard procedures (TFA/CH2Cl2; evapn; EtOAc/satd NaHCO3; dry; evapn.) to yield the free amine, (9H-fluoren-9-yl)methyl (3S,4R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carbonyl)pyrrolidin-3-ylcarbamate (139E): ESI-MS: m/z 608.6 (MH+). 1H NMR (400 MHz, MeOH-d4) δ ppm 1.66 (m, 1H) 1.7-2.3 (m, 5H) 4.21-4.25 (m, 2H) 7.1-7.6 (m, 8H). HPLC retention time, T=0.817 min, STDTFA-2 method.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 80 °C

Procedure:
A solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (1.0 g, 5.32 mmol) in carbon tetrachloride (10.6 mL) is added to polymer-supported triphenylphospine (3.5 g, 3 mmol/g, 10.6 mmol) at room temperature. The reaction is heated for 3 h at 80° C., cooled to room temperature, filtered, and the solids washed with dichloromethane. The filtrate is concentrated in vacuo to yield the title compound, 0.79 g (72%), as a clear, orange oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br>C1COCC1>[CH:5]1[C:4]([C:2]([CH2:1][Br:11])=[O:3])=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(O)cc1

Procedure:
4-Hydroxyacetophenone (25 g) was treated with bromine (9.5 mL) dropwise over 15 minutes in THF (60 mL) at room temperature and stirred until the color was consumed. The whole was carefully poured into saturated sodium bicarbonate solution until basic. The aqueous layer was extracted with ether (3×100 mL) and the ether layer was washed with saturated sodium bicarbonate solution (100 mL) followed by 5% aqueous sodium bisulfite (100 mL), H2O (100 mL) and finally saturated brine solution (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide an oil (30 g) of crude material used in the preparation of thiazoles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C[C@H](C(O)=O)C1C=CC2C=C(OC)C=CC=2C=1.O[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([O:16][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:15])[CH:7]=[CH:6]2
Reactant: ON1CCCCC1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)ON3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To 1.15 g (0.005 mol) of (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, i.e., naproxen, in 50 ml of ethyl acetate was added 0.53 g (0.005 mol) of N-hydroxypiperidine in 20 ml of ethyl acetate and 1.1 g (0.005 mol) of dicyclohexylcarbodiimide. A suspension formed immediately. After 0.5 hour, the suspension was filtered and the residue of dicyclohexylurea (0.6 g) was discarded. The filtrate was concentrated and that residue was suspended in 200 ml of ether and filtered. The ether filtrate was concentrated and that residue was crystallized from 20 ml of cyclohexane. The crystals from cyclohexane were filtered and identified as the acylurea by-product. The cyclohexane solution was concentrated to 5 ml and diluted with 5 ml of heptane to give 0.84 g (mp 95°-97° C., 54% yield) of the desired acylated hydroxylamine (C). The crude product was recrystallized from heptane to give analytically pure product: TLC (silica gel, ether) Rf 0.51; IR (KBr) 1735 cm-1 (s) (C=O), NMR (CDCl3)δ7.8-7.0 (m, 6, aromatic-H), 3.9 (s, 3, CH3 --O), 3.8 (q, 1, J=7 Hz, CH--CH3), 3.5-2.3 (m, 4, CH2N), 1.57 (d, 3, J=7 Hz, CH3 --CH) and 2.0=0.9 (m, 6, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N+:18]([O-])=O)[CH2:8][CH2:7]1>C(O)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NC1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Platinum (IV) oxide (15 mg, 0.07 mmol) was added to a solution of 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (187 mg, 0.50 mmol) in glacial acetic acid (5 ml). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was then filtered through a pad of celite. The filtrate was made basic with a 15% sodium hydroxide solution and the product was extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)-piperazine (119 mg) as an oil.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:16][N:17]([CH:19](O)[CH2:20]CC)[CH3:18]>>[C:1]([O:14][CH2:15][CH2:20][CH2:19][N:17]([CH3:18])[CH3:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC
Reactant: CCCC(O)N(C)C
Product: CCCCCCCCCCCC(=O)OCCCN(C)C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a 50-mL conical bottom plastic vial was added methyl laurate (38.5 mmol), dimethylaminobutanol (46.2 mmol, 1.2 eq), and Novozym 435 (400 mg). A syringe was inserted through the cap and two additional holes were punched for gas to exit. Nitrogen was bubbled at a rate sufficient to mix the contents. The vial was placed in a heating block set to 65° C. The reaction was monitored by GC/MS to observe the disappearance of starting material. The reaction was complete after approximately 24 hours. The reaction mixture was allowed to cool. The Novozym 435 was removed by filtration to afford the product as a pale, yellow oil (9.2 g; 67% yield) without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1>>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:5]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COCc1n[nH]cc1C(=O)OC
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(=O)OC
Yield: 51.6 %

Procedure:
Using methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (7.4 g) synthesized above and 2-chloro-5-trifluoromethylpyridine (5.8 g) and in the same manner as in Example 1(4), the title object compound (5.2 g, 38%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([SH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br-].[CH2:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:17][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(S)cc12
Reactant: C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(SC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
1-(1′-Acetyl-5-mercaptospiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (26 mg, 0.076 mmol) was dissolved in dimethylformamide (1 mL). Thereafter, potassium carbonate (32 mg, 0.23 mmol) and cyclopentane bromide (23 mg, 0.15 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=20:1) to obtain 1-(1′-acetyl-5-(cyclopentylthio)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (13 mg, 42%) in the form of a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:12][C@H:13]([OH:16])[CH2:14]Cl)([CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[NH3:17]>C(O)C>[CH2:1]([O:3][P:4]([CH2:12][C@@H:13]([OH:16])[CH2:14][NH2:17])([CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N
Reactant: CCOP(=O)(C[C@H](O)CCl)C1CC=CCC1
Solvent: CCO
Product: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Reaction time: 72 h

Procedure:
A solution of 2.0 g of 3-chloro-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 40 ml of ethanol is placed in an autoclave. 10.0 g of ammonia are introduced under pressure and the mixture is left to stand at room temperature for 72 hours, concentrated to dryness by evaporation, chromatographed on silica gel, stirred at 0° with ethyl acetate/diethyl ether and filtered with suction, yielding 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester, [α]20D =-5.2±0.9 (c=1.07 in methanol).
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[CH3:14].C(NCCCCCCC(OCC)=O)(=O)C.BrCCCCCCC(OCC)=O.ClCCCC(OC(=O)C)CCCCC>>[C:2]([O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[CH3:14])(=[O:1])[CH3:3]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC1CCCCO1
Agent: CCCCCC(CCCCl)OC(C)=O
Agent: CCOC(=O)CCCCCCBr
Agent: CCOC(=O)CCCCCCNC(C)=O
Product: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
The preparation of this compound is accomplished by essentially the same method as described in Example 1, Step A, except that the N-[4-(2-tetrahydropyranyloxy)nonyl]-acetamide of Example 1, Step A is replaced by an equimolar quantity of ethyl 7-acetamidoheptanoate and the ethyl 7-bromoheptanoate is replaced by an equimolar quantity of 1-chloro-4-acetoxynonane (Example A, Step 4). Purification of the product by column chromatography on silica gel gives ethyl 7-[N-(4-acetoxynonyl)acetamido]heptanoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[F:11][C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 60 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 23 mmol), tert-butyl piperazine-1-carboxylate (4.24 g, 23 mmol), palladium diacetate (0.51 g, 2.3 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2.13 g, 3.4 mmol) and cesium carbonate (14.8 g, 45 mmol) in toluene (120 mL) was heated under nitrogen at 60° C. for 20 hours. After cooling to ambient temperature, the mixture was concentrated and the residue was diluted with dichloromethane (300 mL) and washed with water. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 3/1 petroleum ether/ethyl acetate to give the title compound. MS: 348 (M+Na+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:19][C:20]1[C:29](Br)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[NH2:19][C:20]1[C:29]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Temperature: 110 °C
Yield: 700 %

Procedure:
A flask containing a mixture of 4-nitrophenylboronic acid (5.5 g, 32 9 mmol), sodium carbonate (10.3 g, 97 mmol), tetrakistriphenyphosphine palladium(0) (1.86 g, 1.61 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (10 g, 32 3 mmol) was flushed with nitrogen, 1,4-dioxane (60.0 mL) followed by methanol (20 mL) were added, and the reaction heated at 110° C. for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. aq. Sodium bicarbonate solution and brine, dried with sodium sulfate, and the solvents removed. The residue was suspended and a mixture of EtOAc:hexane=1:4 and then filtered to give methyl 3-amino-6-bromo-2-(4-nitrophenyl)isonicotinate (9.3 g, 21 mmol, 66% yield). MS (ESI) m/z 354.04 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.37 (2 H, d, J=8.85 Hz), 7.91 (1H, s), 7.88 (2H, d, J=8.85 Hz), 5.98 (2H, br. s.), 3.98 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>C(OCC)C>[C:11]([C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)#[N:12]
Reactant: Cn1ccc2ccc(C#N)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
1-methyl-1H-indole-6-carbonitrile (1.0 g, 6.4 mmole), a known compound, was dissolved in ethyl ether (Et2O) (25 mL), chilled in an ice bath and treated with oxalyl chloride (0.95 mL, 10.9 mmole, 1.7 equiv.). After removal of the ice bath, yellow solids soon precipitated. This mixture was stirred at room temperature overnight, the solids were then collected and washed with ethyl ether and dried under vacuum for 30 minutes to provide 1.53 g (96%) of (6-cyano-1-methyl-1H-indol-3-yl)oxo-acetyl chloride. This material (1.53 g, 6.2 mmole) along with 2-(1-methyl-1H-indol-3yl)-acetimidic acid isopropyl ester hydrochloride (1.66 g, 6.2 mmole, 1 equiv.) was suspended in CH2Cl2 (100 mL) and cooled in an ice bath. The mixture was treated with Et3N (3.5 mL, 24.8 mmole, 4 equiv.), stirred at 0° for 30 minutes, then at room temperature for an additional 3 hours. The reaction mixture was then diluted with CH2Cl2 (150 mL), washed with H2O (50 mL), and then 0.5N HCl (50 mL). The organic fractions were dried over MgSO4, filtered and evaporated to give a dark oil. The residue was taken up in toluene (30 mL), chilled in an ice bath, then treated with pTsOH(1.3 g, 6.8 mmole, 1.1 equiv.), then stirred at room temperature for 2 hours. The red solids which precipitated were collected, washed with a small volume of toluene, hexane, the H2O, then partitioned between 500 mL CH2Cl2 and 75 mL saturated NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to provide 2 g of a red solid. The solid was washed with cold CH2Cl2, then recrystallized from acetone/hexane to give 938 mg of 1-methyl-3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:13])(=[O:14])[N:11]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1CN(c2cccc(I)c2)S(=O)(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(c3cccc(I)c3)S2(=O)=O)cc1
Reaction time: 0.58 h

Procedure:
The title B compound, 5-(3-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (932 mg, 2.76 mmol) is dissolved in tetrahydrofuran (20 mL) in a 40 mL capacity septum capped vial, stirred under argon balloon. Triphenylphosphine (1.47 g, 5.51 mmol) is added as a solid and stirred until dissolved, then 4-methyoxybenzyl alcohol (0.688 mL, 5.51 mmol) is added by syringe. The stirred reaction is cooled in an ice bath, and diethyl azodicarboxylate (0.867 mL, 5.51 mmol) is added slow dropwise by syringe. The reaction is stirred 16 h and then recooled and added more diethyl azodicarboxylate (0.433 mL, 2.26 mmol). After 5H, the reaction is concentrated in vacuo, then taken up in CH2Cl2 and chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) for 5 min, then to 5:95 over 35 min. Fractions containing product are combined, concentrated and recrystalized with EtOAc/hexanes to yield 5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: 1H-NMR (300 MHz, DMSO-d6) δ 3.76 (s, 3H), 4.79 (s, 2H), 4.88 (s, 2H), 6.92 (d, J=7.5, 2H), 7.27 (t, J=7.5, 1H), 7.33 (d, J=7.5, 2H), 7.39 (d, J=7.5, 1H), 7.63 (d, J=7.5, 1H), 7.67 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6](/[N:7]=[C:8](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)\[CH3:9])=[CH:5][CH:4]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:16][CH:17]=1)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:9]2
Reactant: COc1ccc(/N=C(\C)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CS(C)=O
Product: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
A 100 mL round-bottom flask equipped with a stirrer bar was charged with (E)-4-methoxy-N-(1-phenylethylidene)aniline (10 mmol, 2.25 g), Pd(OAc)2 (0.22 g, 1 mmol, 10 mol %) and Bu4NBr (6.45 g, 20 mmol, 2 equiv), followed by addition of DMSO (50 mL). The flask was quickly evacuated, closed under vacuum, and then refilled with oxygen using an oxygen balloon. The resulting mixture was stirred at 60° C. for 24 h. Upon cooling to room temperature, the reaction mixture was diluted with 25 mL of ethyl acetate, followed by filtration through a pad of silica gel. The filtrate was concentrated under vacuum, and the residue was purified on silica gel to afford the title compound as an off-white solid (1.87 g, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([CH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1)[C:65]([OH:67])=O)=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.C1COCC1.[Li+].[OH-]>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:22]=[CH:21][C:20]4[C:25](=[CH:26][CH:27]=[C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:65](=[O:67])[CH:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[CH:68]6[CH2:73][CH2:72][O:71][CH2:70][CH2:69]6)=[N:17][CH:16]=5)[CH:19]=4)[CH:24]=3)=[CH:29][CH:30]=2)=[CH:38][N:37]=1)=[O:57]
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.26 mmol) in CH2Cl2 (2.5 mL) and MeOH (0.1 mL) was added HCl (in dioxanes, 4 M, 0.7 mL, 2.80 mmol). The solution was stirred at room temperature for 3 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (4 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.12 g, 0.54 mmol), HATU (0.12 g, 0.33 mmol), and DIPEA (0.2 mL, 1.15 mmol) were added. The resulting solution was stirred at room temperature for 1 h. The solution was diluted with THF and LiOH (2.5 M, 0.1 mL) was added. The solution was concentrated to dryness and the crude oil was diluted with DMF and purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide {2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.083 g, 37%). LCMS-ESI+: calc'd for C49H52N8O7: 864.40 (M+); Found: 866.01 (M+H+).