Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:22]=2)=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([NH:1][C:30]2[CH:29]=[CH:28][C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:18]4[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=4)[CH:22]=3)=[CH:32][CH:31]=2)=[CH:7][CH:6]=1
Reactant: Brc1ccc(-c2cccc(-c3ccccc3)c2)cc1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(Nc3ccc(-c4cccc(-c5ccccc5)c4)cc3)cc2)cc1
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
In a drybox, 4-aminobiphenyl (0.542 g) and 4-bromo-1,1′:3′,1″-terphenyl (0.89 g) were combined in a round-bottom flask and dissolved in 10 ml of dry toluene. Tris(tert-butyl)phosphine (0.022 g, 0.11 mmol) and tris(dibenzylideneacetone) dipalladium(0) (0.05 g, 0.055 mmol) were dissolved in 10 ml of dry toluene and stirred for 5 minutes. The catalyst solution was added to the reaction mixture, stirred for 2 minutes and was followed by sodium tert-butoxide (0.32 g, 3.3 mmol). Flask was capped and left to stir in the drybox overnight at room temperature. Next day, reaction mixture was taken out of the box and filtered through a one-inch plug of silica gel topped with celite, washing with 500 ml of dichloromethane. Removal of volatiles under reduced pressure gave a yellow solid. Crude product was purified by trituration with diethyl ether to give 0.85 g (73%) of a white solid. Structure was confirmed by 1H NMR spectroscopy.
Reaction SMILES: C(=O)(O)[O-].[K+].[C:6]1([CH2:12][C:13](Cl)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][CH2:23][CH2:22]2>>[C:6]1([CH2:12][C:13]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[CH2:24][CH2:23][CH2:22]3)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2c(cc1CCN)CCC2
Agent: O=C([O-])O
Agent: [K+]
Product: COc1cc2c(cc1CCNC(=O)Cc1ccccc1)CCC2

Procedure:
Using the procedure of Example 1, but with potassium bicarbonate replacing triethylamine, phenylacetyl chloride was reacted with 5-aminoethyl-6-methoxyindan to produce the desired product. After recrystallization from ether it had a melting point of 135° C.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.Cl[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>C1COCC1>[F:1][C:2]1([F:19])[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]=[C:10]([C:12]2([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]2)[O:11][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:6][CH2:7]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C(CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(=CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
3-(4,4-Difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-1-one (0.200 g, 0.704 mmol) obtained in step 3 was dissolved in THF (2.0 mL). Under ice-cooled condition, DBU (0.117 mL, 0.774 mmol) and chlorotriethylsilane (0.130 mL, 0.774 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with heptane after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→90/10) to give {3-(4,4-difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)prop-1-enyloxy}triethylsilane (0.253 g, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C@H:18]2[O:23][CH:22]([O:24]CC)[CH2:21][C@H:20]([OH:27])[CH2:19]2)=[CH:4][C:3]=1[CH3:28].O.CC(C)=O.C(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C@H:18]2[O:23][CH:22]([OH:24])[CH2:21][C@H:20]([OH:27])[CH2:19]2)=[CH:4][C:3]=1[CH3:28]
Reactant: CCOC1C[C@H](O)C[C@@H](/C=C/c2c(C)cc(C)cc2-c2ccc(F)c(C)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(/C=C/[C@@H]2C[C@@H](O)CC(O)O2)c(-c2ccc(F)c(C)c2)c1
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a solution of the crude mixture of anomers, (4R,6S)-(E)-6-[2-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)ethenyl]-2-ethoxy-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran (0.83 g, 0.0021 mole) in glacial acetic acid (36 ml) was added water (12 ml). Additional acetic acid (3 ml) was added and the solution allowed to stand for 24 hours at which time tlc (silica gel, 5% acetone-CH2Cl2) indicated the reaction was essentially complete. The reaction mixture was poured into water (800 ml) containing sodium hydroxide (50 g) and extracted with ether (1200 ml). After washing the ether extract with water, drying (MgSO4) and evaporating there was obtained crude lactol product (0.68 g). The crude product was purified by flash chromatography (45 mm id column, 4% actone --CH2Cl2) to give 0.36 g of product which showed a single spot on tlc. 360 MHz H' -NMR in DCCl3 confirmed the presence of two hydroxy anomers in the product.
Reaction SMILES: [NH2:1][CH:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].N[C@H](C(O)=O)C(C)(C)C.N[C@@H](C(N)=O)C(C)(C)C>>[NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(N)C(N)=O
Agent: CC(C)(C)[C@@H](N)C(N)=O
Agent: CC(C)(C)[C@H](N)C(=O)O
Product: CC(C)(C)[C@H](N)C(N)=O

Procedure:
In the same way as in example VIII, an incubation was carried out with DL-tertiary leucine amide. Analysis of the remaining reaction mixture after 8 hours showed that both L-tertiary leucine and D-tertiary leucine amide with an e.e. of ≥99% were present in the reaction mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([CH:29]=[CH2:30])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C3CCCC3)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.5 g, 3.386 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.625 g, 4.063 mmol) and Pd(PPh3)4 (0.392 g, 0.034 mmol) in 1,4-dioxane (15 mL) and purged with argon for 10 min. A solution of 2M Na2CO3 (1.29 g, 12.18 mmol) was then added to it before a further argon purge for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-vinyl-1H-indazole-4-carboxamide (0.9 g, 68.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[In].[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([F:18])[F:17])[CH3:13].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[C:16]([F:18])([F:17])[C:15]([O:14][CH2:12][CH3:13])=[O:20])[CH:9]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)C(O)c1cc(Br)ccc1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To an ice cooled solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.2 mmol) in dry DMF (14 mL), Indium powder (8.48 g, 73.7 mmol) was added and stirred for 15 min. ethylbromodifluoroacetate (9.48 ml [14.98 g], 73.7 mmol) in dry DMF (10 mL) was added to the resultant reaction mixture and temperature of the reaction mixture was allowed to warm to rt (30° C.). Stirring continued for 24 h. TLC analysis of the reaction mixture indicated the product formation. Reaction mixture was treated with aqueous saturated NH4Cl solution and the crude product was extracted with ethyl acetate (500 mL) by washing with water, brine and the organic layer was dried over anhydrous Na2SO4. The organic layer was concentrated and the crude product was purified by column chromatography on silica gel using 4% Ethyl acetate in Hexane to obtain title compound as a colorless thick liquid. Yield=12.0 g (75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (2.29 g) in methanol (10 mL) was added dropwise 2M trimethylsilyldiazomethane solution in hexane (11.9 mL) under ice-cooling. The reaction mixture was concentrated, and to the residue was added hexane. The precipitated crystals were collected by filtration, and the filtrate was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=9/1 to 7/3). The product and the crystals obtained above were combined to give methyl 1-(tert-butoxycarbonylamino)-cyclopentane-carboxylate (2.49 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C2=CC(=O)c3ccccc3S2(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(c2ccc(O)cc2)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 2-(4-acetoxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one (260 mg, 0.79 mmol) in MeOH:THF (5 mL: 5 mL), K2CO3 (133 mg, 0.95 mmol) was added and stirred for 2 h at rt Then the reaction mixture was neutralized by dilute HCl and extracted by EtOAc, the combined organic layer was washed with water, brine, dried and concentrated to give a crude product, which was purified by column chromatography using 50% EtOAc in hexane, to give 134 mg (59%) of 2-(4-hydroxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one. MS (ES) m/z: 286.05 (M), 285.01 (M−1); Mp. 222-224° C.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CC)CO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCCC(CC)CO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCC(CC)CCCC
Reaction time: 0.67 h
Yield: 98 %

Procedure:
500 g (2.01 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1047 g (8.04 mol) of 2-ethyl-1-hexanol (made by Wako Pure Chemical Industries, Ltd., Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and water-containing 2-ethyl-1-hexanol was distilled off with the pressure in the system at from 40 to 20 kPa. This state was maintained for 2 hours, and then the pressure in the system was further reduced, and excess 2-ethyl-1-hexanol was distilled off. Once distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 750 g of reaction liquid was obtained in the flask. According to 119Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-bis(2-ethylhexyloxy)-distannoxane was obtained at a yield of 98% based on the dibutyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetrabutyl-1,3-bis(2-ethylhexyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C@@H:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C@@H:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](N2CCOCC2)CN1C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](N2CCOCC2)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4S)-1-t-butoxycarbonyl-N-t-butyl-4-morpholino-L-prolinamide (prepared as described in Preparation 6) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 115°-117° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[CH:13][N:14]2[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(C)(C)C>CCCCCCC.C(OCC)(=O)C.C(O)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([NH2:7])=[CH:9][CH:10]=2)[N:14]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cccnc3)c2c1
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cccnc3)c2c1
Yield: 31.9 %

Procedure:
[3-(2-Nitro-phenylsulfanyl)-1-pyridin-3-ylmethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (Example 3, step iv; 5.96 g, 12.5 mmol) was deprotected to give, after column chromatography (heptane/ethyl acetate/ethanol 4:4:1), the title compound (1.50 g). 1H-NMR (CDCl3) δ 8.55-8.60 (m, 2H), 8.26 (dd, 1H, J=8.5 and 1.5 Hz), 7.42 (dt, 1H, J=8.0 and 1.5 Hz), 7.24-7.33 (m, 3H), 7.17 (ddd, 1H, J=8.0, 7.0 and 1.0 Hz), 7.01 (dd, 1H, J=8.0 and 1.5 Hz), 6.60 (m, 2H), 6.59 (s, 1H), 5.30 (s, 2H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:25]1[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][C:26]=1[OH:35]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:35][C:26]1[CH:27]=[CH:28][C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:25]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc2c(c1)CCCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 95.6 %

Procedure:
As described in Example 44, 8.28 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 3.4 g of 5,6,7,8-tetrahydro-2-naphthol to give 9.2 g of product as a viscous oil.
Reaction SMILES: C[N:2]([CH3:16])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.Cl.NC1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH2:26])=[O:25]>C(O)(=O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([C:24]([NH2:26])=[O:25])=[C:16]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc([N+](=O)[O-])c3)ccnc12
Yield: 73 %

Procedure:
A stirred mixture of 18.0 g of 3-dimethylamino-3'-nitroacrylophenone (prepared as described in Example 10) and 10.30 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. Upon standing at room temperature a crystalline precipitate was formed. The precipitate was collected, washed with saturated sodium bicarbonate solution and then with water to give 13.1 g of product. The material was recrystallized from methanol-chloroform by the addition of hexane and by scratching to give 8.7 g of the product of the example as yellow crystals, mp 282°-284° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH:28](CC[O-])[CH:29]([C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[OH-].[Na+]>O>[OH2:15].[N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH2:28][CH:29]([C:30]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c1cc(F)cc3C(CC[O-])C2C(=O)N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c(cc(F)cc31)CC2C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Heat a slurry of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine ethanolate (200.6 mg) in water (25 mL) to 75° C. for 0.5 hours. Add 0.72 mL of 1N HCl and continue to heat for 0.75 hours. Rapidly add 0.72 mL of 1N NaOH. Allow the suspension to cool to room temperature. Collect the solid using vacuum filtration through Whatman #1 paper, rinse with 20 mL deionized water and allow to dry loosely covered for 2 days.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), isobutyryl chloride (59 mg, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 851 as a white solid (57 mg, 21%). LCMS (method I): RT 3.69 min, [M+H]+ 531.4. 1H NMR (DMSO, 400 MHz): δ 8.01-8.00 (1 H, m), 7.63-7.62 (1 H, m), 7.27-7.23 (2 H, m), 4.40 (1 H, d, J=13.34 Hz), 4.25 (4 H, brd s), 3.94 (1 H, d, J=13.78 Hz), 3.77-3.74 (7 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.01 (1 H, t, J=13.02 Hz), 2.87-2.85 (3 H, m), 2.50-2.50 (1 H, m), 2.12-2.08 (1 H, m), 1.77-1.73 (2 H, m), 1.33 (3 H, t, J=7.44 Hz), 1.29-1.07 (2 H, m), 1.00-0.98 (6 H, m)
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1[N:15]1[C:19](=[O:20])[CH:18]=[C:17]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[N:16]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]>ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1[N:15]1[C:19](=[O:20])[C:18]([Cl:4])=[C:17]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[N:16]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(=O)OCC)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2c(Cl)c(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(=O)OCC)c1

Procedure:
4.45 ml (0.055 mole) of sulfuryl chloride are added dropwise in 15 min at -50° C to a cooled solution of 34.4 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-2-ethoxycarbonyl-3-(2-chloro-5-myristoylamino-anilino)-3-pyrazolin-5-one (compound 19) in 100 ml dichloromethane.