Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25](C3N=CN(C)C=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Cl.[OH2:36]>C(#N)C.OO>[CH3:3][CH2:2][CH2:1][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:23])=[O:36])=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:4]3[N:8]([CH3:9])[C:7]4[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=4[N:5]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Reactant: O
Agent: Cl
Agent: OO
Solvent: CC#N
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 156 mg of NaClO2.4H2O in 1 mL of water was added dropwise by canilla to a stirred mixture of 4′-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxaldehyde (230 mg) in 1 mL of acetonitrile, 0.16 ml of 10 solution of NaH2PO4 in water and 0.23 mL of 30% H2O2 at the temperature 10° C. pH of the mixture was adjusted to 2 with concentrated hydrochloric acid. Stirring was continued for 1.5 h at room temperature. Reaction mixture was poured in 1.2 mL of water, stirred for 15 minutes, product filtered, washed with water and dried in vacuo to yield 210 mg of telmisartan.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:7][C:8]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>>[ClH:1].[ClH:1].[CH3:7][C:8]1[C:9]([NH2:10])=[CH:11][CH:12]=[CH:13][C:14]=1[NH:15][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: ClC1=NCCC1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: Cc1c(N)cccc1NC1=NCCC1
Product: Cl

Procedure:
The title compound (20.9 g) was prepared by the methods of Examples 8 and 9 using 2-chloro-1-pyrroline, prepared as in Example 1, and 30.0 g of 2-methyl-3-nitroaniline. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:29])[C:17]3[C:30](=[O:34])[NH:31][C:32](=[O:33])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:35])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[Cl:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:18]1[C:17]2[C:30](=[O:34])[NH:31][C:32](=[O:33])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([OH:35])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:7][CH2:6][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:20]=2[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCOS(C)(=O)=O
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCN1CCOCC1
Yield: 81 %

Procedure:
Reaction of 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6 (1H)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6-methoxyphenyl, n=2, mesylate) (114) prepared as described in example 66 with morpholine using the procedure described in example 179 of Scheme 3 gave 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VIII; Ar=2-chloro-6-methoxyphenyl, n=2, Z=4-morpholinyl) (115) in an 81% yield as a yellow powder; mp 185° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 9.34 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.3, 8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.14–7.10 (m, 2H), 4.53 (t, J=6.1 Hz, 2H), 3.66 (s, 3H), 3.41 (t, J=4.5 Hz, 4H), 2.64 (t, J=6.1 Hz, 2H), 2.37 (m, 4H). Found: C, 63.57; H, 4.71; N, 8.06. C27H24ClN3O5.1/4H2O requires C, 63.53; H, 4.84; N, 8.23.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].[Na].[C:13]1([CH:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]2[CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(=O)(=O)C>CC(C)CC(=O)C>[Cl:1][C:2]1[C:3]([O:11][CH:22]2[CH2:23][N:20]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1c(Cl)ccc2c1CCC2
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(c1OC1CN(C(c3ccccc3)c3ccccc3)C1)CCC2
Temperature: 120 °C
Reaction time: 64 h
Yield: 91.4 %

Procedure:
2 g of 5-chloro-2,3-dihydro-1H-inden-4-ol were stirred in 75 ml of a 2N sodium hydroxyde solution for 1 hour. To the clear solution were added 75 ml of 4-methyl-2-pentanone and 3.76 g of 1-(diphenylmethyl)-3-methanesulfonyloxy-azetidine and the mixture was heated in an oil bath at 120° C. for 3.5 hours. Then another 2 g of mesylate were added and heating was continued for 64 hours. The upper layer was separated and washed with water. Evaporation in vacuo and chromatography with toluene/ethyl acetate (95:5) gave 4.22 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl )-azetidine as a clear oil that solidified spontaneous. M.S. (C.I.) (M/Z): 391 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:33])[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][NH:18]C(=O)OCC[Si](C)(C)C)=[O:15])[CH2:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1.ClC1C=CC(C(NC(C(C)C)CC(N2CC[C@@](C3C=CC(Cl)=CC=3)(O)C(C)(C)C2)=O)=O)=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[NH2:18][CH2:17][C@H:16]([CH:28]([CH3:30])[CH3:29])[C:14]([N:11]1[CH2:12][CH2:13][C@@:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:33])[C:9]([CH3:31])([CH3:32])[CH2:10]1)=[O:15]
Reactant: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: CC(C)C(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](CN)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl(S)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)-3-methylbutylcarbamate (110 mg, 0.221 mmol) in THF (1 mL) was added 1 equivalent of 1 M-tetra-N-butylammonium fluoride (0.221 mL, 0.221 mmol). The resulting mixture was stirred at room temperature for 1.5 hrs. After this time, the reaction was analyzed by LC/MS, which showed that the reaction was very slow. An additional 4 equiv. of TBAF (0.88 ml) was added and the mixture was stirred at room temperature for an additional 24 hour. After this time, the reaction mixture was added to EtOAc, washed with water and brine, dried over Na2SO4 and evaporated to give an oily residue. The oily residue was purified by Combiflash chromatography (24 g silica gel) with elution by 6:4 EtOAc-hexane to give the title compound (85.3 mg). MS (ESI+)=353.13 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:28])[CH2:37][CH2:36]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
10.9 g of N,N'-carbonyldiimidazole were added to a solution of 25.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 200 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 10.9 g of 1-(2-hydroxyethyl)piperazine in 50 ml of dry acetonitrile was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 45 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, after which it was diluted with 800 ml of ethyl acetate. The dilute solution was washed, in turn, with water (200 ml, three times) and an aqueous solution of sodium chloride (150 ml, once). The resulting ethyl acetate solution was concentrated by evaporation under reduced pressure to a volume of 100 ml, and the crystals which precipitated were collected by filtration, to give 28.6 g of the title compound as colorless crystals, melting at 140°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.ClC1N=C(OC)N=C([O:23][CH3:24])N=1.[CH3:25][N:26]1CCOCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:26]([O:23][CH3:24])[CH3:25])=[O:10])=[CH:11][CH:12]=1
Reactant: CN1CCOCC1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a solution of Terephthalic acid monomethyl ester (5.4 g, 30 mmol) and 2-chloro-4,6-dimethoxy-[1,3,5]triazine (7.9 g, 45 mmol) in THF (300 mL) is added N-methyl morpholine (4.95 mL, 45 mmol), the mixture is stirred at room temperature overnight. Additional N-methyl morpholine (4.95 mL, 45 mmol) is added, followed by the addition of O, N-dimethyl-hydroxylamine HCl salt (3.51 g, 45 mmol). The reaction mixture is stirred overnight, and filtered through celite. The filtrate was concentrated and purified by column chromatography on silica gel (hexane/ethyl acetate) giving the title compound (6.8 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]/[C:8]([CH3:11])([CH3:10])[CH3:9])CCC.Br[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:8]([CH3:9])([CH3:10])/[CH:7]=[CH:6]/[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: CCCC[Sn](/C=C/C(C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1noc(/C=C/C(C)(C)C)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(E)-Tributyl(3,3-dimethylbut-1-en-1-yl)stannane (1194 mg, 0.8 mmol) and ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (187 mg, 0.8 mmol) were dissolved in dioxane (6 mL) and the mixture was degassed thoroughly, refilling with nitrogen. Pd(Ph3P)4 (92 mg, 0.080 mmol) was added and the mixture was stirred at 100° C. for 16 hours. The crude reaction mixture was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1>C(Cl)(Cl)Cl>[O-:6][N+:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[N:12]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2cnc3ccccc3c21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1cnc2c[n+]([O-])c3ccccc3c21

Procedure:
3-Chloroperoxybenzoic acid (3.71 g of ˜60%, 13.48 mmol) was added in small portions over a period of 20 minutes to a solution of tert-butyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (4.0 g, 12.25 mmol) in chloroform (175 mL). After 1 hour the reaction was quenched with aqueous 1% sodium carbonate solution. The layers were separated. The organic layer was washed with aqueous 1% sodium carbonate solution (3×100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The organic layers were combined and concentrated under reduced pressure to provide crude tert-butyl 3-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][N:5]=1.CN(C)C(=O)C.[SH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>CC(C)=O>[ClH:2].[CH3:10][C:9]1[C:4]([CH2:3][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.71 g (0.0459 mole) of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride were suspended in 322 ml of acetone in the presence of 2.52 ml N,N-dimethylacetamide. Then 7.24 g (0.0597 mole) of 2-mercaptobenzimidazole were added. The mixture was heated to reflux and stirred for 5 hours. After cooling to room temperature, the resulting suspension was filtered to obtain the wet product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(OC(C)(C)C)=O)[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[CH2:19][O:18]1.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][N:17]2[C:21](=[O:22])[C:20]([CH3:23])([CH3:24])[CH2:19][O:18]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.1 %

Procedure:
To a stirred solution of 2.0 grams (0.006 mole) of 2-[2-chloro-4-(1,1-dimethylethoxycarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone in 10 ml of methylene chloride was added dropwise a solution of 10 ml of trifluoroacetic acid in 10 ml of methylene chloride. Upon completion of addition the reaction mixture stirred at ambient temperature for 3.5 hours. The reaction mixture was slurried with 50 ml of water and neutralized with a saturated aqueous solution of potassium carbonate. A solid precipitate was collected by filtration to give 1.3 grams of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 106°-108° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:17][NH:18][C:19]2[N:27]=[C:26]([CH2:28][NH:29][C:30]([NH:32][CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])=[O:31])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:39]2[O:43][C@H:42]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])[C@@H:41]([OH:49])[C@H:40]2[OH:50])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(OCC)(=O)C>[NH3:18].[C:1]([N:35]([CH:36]([CH3:37])[CH3:38])[CH2:34][CH2:33][NH:32][C:30]([NH:29][CH2:28][C:26]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@@H:39]2[O:43][C@H:42]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])[C@@H:41]([OH:49])[C@H:40]2[OH:50])=[C:19]([NH:18][CH2:17][CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:27]=1)=[O:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCNC(C)C)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN(C(=O)c4ccccc4)C(C)C)nc32)[C@H](O)[C@@H]1O
Product: N
Reaction time: 96 h
Yield: 77.8 %

Procedure:
Benzoyl chloride (19 mg, 0.14 mmol) was added to a stirred solution of (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (80 mg, 0.12 mmol) (Preparation 12) and triethylamine (0.034 ml, 0.25 mmol) in ethyl acetate (5 ml) and N′-methylpyrrolidinone (0.2 ml) at room temperature. The reaction mixture was stirred for 96 hours, washed with water (2 ml) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 0.88 concentrated aqueous ammonia (90:10:1 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (80:20:3 by volume) to give the title compound as a foam (35 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]([C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:43]3[CH:44]=[C:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[CH:40]=[CH:41][C:42]=3[O:48][CH3:49])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 80 °C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 25 mg; 0.041 mmol), (5-tert-butyl-2-methoxyphenyl)boronic acid (11.1 mg; 0.053 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (2.7 mg; 0.0041 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) were combined in a sealed tube and heated at 80° C. for 1.5 h. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-30% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-tert-butyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=648.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.83 (m, 2H), 7.78 (s, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.44-7.36 (m, 2H), 7.18 (dd, J=6.7, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.20 (d, J=16 Hz, 1H), 5.16 (d, J=11.2 Hz, 1H), 4.38 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 3.41-3.34 (m, 1H), 2.29-2.24 (m, 1H), 1.88-1.81 (m, 1H), 1.32 (s, 9H), 1.02 (d, J=6.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[S:34][C:35]1[NH:36][CH:37]=[CH:38]C=1)CCC>>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:35]4[S:34][CH:38]=[CH:37][N:36]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)Sc1ccc[nH]1
Product: Cn1cc(C2=C(c3cn(C)c4cc(-c5nccs5)ccc34)C(=O)NC2=O)c2ccccc21
Yield: 22.8 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (25 mg, 23%) was prepared from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (108 mg, 0.25 mmol) and 2-(tributylstannyl)thioazole (140 mg, 0.375 mmol).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH:11]S(C(C)(C)C)=O)[CH2:10][O:9][CH2:8]1>O1CCOCC1.CO>[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH2:11])[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2nccs2)COC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
A 4.0 M solution of hydrochloric acid (117 μL, 467 μmol) in dioxane was added to a solution of 2-Methyl-propane-2-sulfinic acid (3-thiazol-2-yl-oxetan-3-yl)-amide (Example 32a, 81 mg, 311 μmol) in methanol (0.5 mL) at 0° C. The mixture was stirred at 0° C. for 5 min before the solvents were removed under reduced pressure. The resulting white solid was triturated with diethyl ether and filtered off. The solid was further washed with diethyl ether and dried under high vacuum to yield the title compound (42 mg, 70%) as a white solid. MS (ESI, m/z): 157.1 (M+H+).
Reaction SMILES: CO.O.Cl.CS[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19](OC)([O:25]C)[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]>C(Cl)Cl>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:14][CH:15]=1)=[O:25]
Reactant: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2cccs2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Yield: 105.6 %

Procedure:
Methanol (4 ml), 1 ml of water, and 0.2 ml of conc. hydrochloric acid were added to 405 mg of methyl α-methylthio-α-[p-[dimethoxy(2-thienyl)methyl]phenyl]propionate, and the resulting mixture was heated under reflux for 30 minutes. After the mixture was cooled and shaken with 50 ml of methylene chloride, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 320 mg of methyl α-[p-(2-thienylcarbonyl)phenyl]propionate as a colorless oil in a yield of 90%.
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19]C=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=CC=2)C=CC=CC=1.[Li]CCCC.[CH2:27]([C:29]1[CH:30]=[N:31][C:32]([N:35]2CCC([C@H]3C[C@H]3C=O)CC2)=[N:33][CH:34]=1)[CH3:28]>C1COCC1>[CH2:27]([C:29]1[CH:30]=[N:31][C:32]([N:35]2[CH2:17][CH2:16][CH:15]([C@H:8]3[CH2:9][C@H:14]3[CH:13]=[CH2:12])[CH2:20][CH2:19]2)=[N:33][CH:34]=1)[CH3:28]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3C=O)CC2)nc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@@H]1C1CCN(c2ncc(CC)cn2)CC1
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred suspension of triphenylmethyl phosphonium bromide (10.5 g, 29.4 mmol) in THF (80 mL) was added n-BuLi (11.4 mL of a 2.5M solution in hexanes, 28.4 mmol) dropwise. Upon stirring the resulting orange suspension for 45 min at −78° C., a solution of the product of step B (3.8 g, 14.7 mmol) in THF (25 mL) was added dropwise. The cold bath was removed and the mixture was stirred at RT for 2 h before being quenched with a saturated aqueous solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the desired alkene. MS (ESI) m/z 258 [M+H]+.