Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH2:12]([O+](CC)CC)[CH3:13]>ClCCCl>[F:7][B-:8]([F:11])([F:10])[F:9].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: Cn1ccnc1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCn1cc[n+](C)c1

Procedure:
22.3 ml of N-methylimidazole and 120 ml of 1,2-dichloroethane were introduced into a 250 ml glass flask under an argon atmosphere. 53.2 g of triethyloxonium tetrafluoroborate was added in small portions. The reaction medium was observed to heat up slightly and the solvent was then refluxed for 1 hour 30 minutes. The molten salt formed was colorless, non miscible and denser than the 1,2-dichloroethane. It was separated by simple decanting and drawn under vacuum using a vane pump.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]1([C:14](Cl)=O)[CH2:13][CH2:12]1>O1CCOCC1.CN(C)C=O>[CH:11]1([C:14]2[N:1]=[C:2]3[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]([OH:9])[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(O)n2nc(C3CC3)nc2n1

Procedure:
To a solution of Intermediate 1 (0.5 g, 3.57 mmol) in a mixture of 1,4-dioxane (4 mL) and N,N-dimethylformamide (1 mL), cyclopropanecarbonyl chloride (ALDRICH, 0.49 mL, 5.35 mmol) was added and the resulting mixture was heated under reflux overnight. The reaction was then concentrated under vacuum yielding a pale yellow solid which was purified by flash chromatography (Si, eluting with DCM:MeOH mixtures, gradient from 100:0% to 90:10%) to yield a beige solid which was re-purified by flash chromatography (Si, eluting with DCM:MeOH mixtures from 100:0 to 85:15%). The title compound was obtained as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
To an ice-cooling suspension of lithium aluminium hydride (1.79 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 4'-methylbiphenyl-2-carboxylic acid (5.0 g) in tetrahydrofuran (30 ml). The mixture was stirred for 17 hours at room temperature. To the reaction mixture were added ethyl acetate (10 ml) and water (50 ml), and insoluble materials were removed by filtration through celite. The filtrate was concentrated to dryness, and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as colorless syrup (3.95 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15][CH3:16])=[N:13][CH2:14][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[K+].[Br-]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15][CH3:16])=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: CSC1=NCC2CN=C(c3ccccc3F)c3cc(Cl)ccc3N12
Agent: [Mn+4]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 2.8 g (7.8 mmol) of the end product of Example 24 and 13 g of activated manganese dioxide in 500 ml of toluene was refluxed overnight. The mixture was filtered through Celite, evaporated in vacuo and the residue treated with ether-petroleum ether to give a tan solid. Recrystallization from methylene chloride-ether gave a white powder, mp 180°-181°: Ir (KBr) 1610 and 1480 cm-1 ; nmr (CDCl3) 2.60 δ (s, 3H), 4.10 (d, J=12Hz, 1H) 5.20 (d, J=12Hz, 1H) and 6.90-7.80 (m, aromatic, 8H); uv λ max 219 nm (ε=36500), infl. 242 (19900) and 270 (8700); mass spectrum m/e 357 (M+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:9][CH:10]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: Nc1ccnn1-c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1-c1ccccc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 15.9 g. (0.10 mole) of 1-phenyl-5-aminopyrazole and 21.6 g. (0.10 mole) of diethyl ethoxymethylenemalonate was heated at 115-120° in an oil bath for 2 hours. After cooling, the crystalline mass was recrystallized from hot hexane containing 1% of ethanol. Cooling to room temperature and filtering gave 24.8 g. (75%) of off-white crystals, m.p. 96-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.[I-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([CH:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:27][CH2:26]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(C=CCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C=CCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 gram (0.002 mole) of 3-(4-nitrophenyl)-2-propenyl chloride in 5 mL of dimethyl sulfoxide was added to a solution of 0.7 gram (0.002 mole) of N-[bis(4-fluorophenyl)methyl]piperazine in 10 mL of dimethyl sulfoxide. To this was added 0.1 gram (0.0005 mole) of sodium iodide as a catalyst. Upon completion of the addition 1.2 grams (0.010 mole) of N,N-diisopropylethylamine was added dropwise. To effect solution the reaction mixture was then warmed to 50-80° C., where it stirred for four hours . After this time the reaction mixture was cooled to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into 50 mL of aqueous saturated sodium bicarbonate solution and then extracted with three 50 mL portions of diethyl ether. The combined extracts were washed with 75 mL of aqueous saturated sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a crude oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.5 gram of of N-[3-(4-nitrophenyl)-2-propenyl]-N′-[bis(4-fluorophenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(OCC)(=O)C.N1C=CC=CC=1>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 0.5 h

Procedure:
2-acetyl-1,2,3,4-tetrahydro-β-carboline was prepared as follows: 1 g of 1,2,3,4-tetrahydro-β-carboline (Sigma) was dissolved in a minimum of ethyl acetate, and pyridine 3 mL) was added along with acetic anhydride (1.5 mL). After 30 minutes, the mixture was dried and the resulting 2-acetyl-1,2,3,4-tetrahydro-β-carboline was recrystallized from acetone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:19])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=2)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl.O>[C:34]1([O:33][C:31](=[O:32])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:19])[N:8]=3)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2N)n1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 131.6 %

Procedure:
A solution of Intermediate 140b (129 mg, 0.41 mmol) in DCM (4.1 mL) was treated with pyridine (0.046 mL, 0.57 mmol) and the mixture was cooled 0° C. Phenyl chloroformate (0.066 mL, 0.53 mmol) was added and the resulting mixture was stirred at RT for 16 h. The mixture was cooled to 0° C. and treated with pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate (0.015 mL, 0.12 mmol) and stirred at RT for a further 1.75 h. Once again the mixture was cooled to 0° C. and treated with pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate (0.015 mL, 0.12 mmol) and stirred at RT for 1.75 h. The mixture was diluted with water and the phases were separated. The aqueous layer was extracted with DCM (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a yellow gum (236 mg). Trituration with ether and filtration of the resulting solid gave the title compound as a white solid (75 mg, 39%). LCMS (Method 3): Rt 3.21 min, m/z 438.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[CH3:25][C:26]1([CH3:33])[CH2:31][C:30](=O)[CH2:29][CH2:28][O:27]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:30]2[CH2:29][CH2:28][O:27][C:26]([CH3:33])([CH3:25])[CH2:31]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: CC1(C)CC(=O)CCO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CC(Nc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CCO1
Temperature: 22 °C
Reaction time: 12 h
Yield: 3.1 %

Procedure:
A solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (130 mg, 0.4 mmol), 2,2-dimethyldihydro-2H-pyran-4(3H)-one (52 mg, 0.4 mmol) and AcOH (0.1 mL) in MeOH (10 mL). The mixture was stirred at 22° C. for 12 h, then NaBH3CN (76 mg, 1.2 mmol) was added and the resulting mixture was stirred at 22° C. for 2 h. The reaction mixture was concentrated and quenched with water. The aqueous mixture was extracted with DCM, the combined organic layers were concentrated and the residue was purified by prep-HPLC to give the title compound (5.5 mg, Yield 3.1%). 1H NMR (CD3OD, 400 MHz): δ 8.42 (brs, 1H) 7.00-7.33 (m, 7H) 6.84 (d, J=7.8 Hz, 1H) 4.21-4.41 (m, 3H) 3.40-3.92 (m, 8H) 3.11-3.20 (m, 3H) 1.91-2.07 (m, 2H) 1.18-1.44 (m, 8H). LCMS (m/z): 438.3 (M+1).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:26]=3)[CH:18]=2)[CH2:12][C:13]([O:15]C)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>>[C:1]1([S:7]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:26]=3)[CH:18]=2)[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OCc2cccc(NC(=N)N)c2)c1
Agent: [Li+]
Agent: [OH-]
Product: N=C(N)Nc1cccc(COc2cccc(C(CC(=O)O)NS(=O)(=O)c3ccccc3)c2)c1

Procedure:
Corresponding to Example 4g, 471 mg of (8h) were hydrolysed using lithium hydroxide. A white solid was obtained (yield: 253 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20][Br:21])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(CBr)c(Br)cc21
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Under a nitrogen stream, a solution of 1-benzenesulfonyl-6-bromo-5-methyl-1H-indole (40 mg, 0.11 mmol), N-bromosuccinimide (NBS) (22 mg, 0.12 mmol) and 2,2′-azobis(isobutyronitrile) (AIBN) (1 mg, 0.01 mmol) in carbon tetrachloride (0.5 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)), to thereby obtain the titled compound (22 mg, 45%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]12C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[CH:8]2>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCC
Reactant: C1=CC2CCC1C2
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC=CCCCCCCCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, an anhydrous toluene solution (2 ml) containing 1-hexene (75 μl: 6.0 mol %) and a Grubbs I catalyst (4.1 mg: 0.05 mol %) was added to an anhydrous toluene solution (23 ml) containing the norbornene monomer J (1.60 g: 10.0 mmol), and stirred at room temperature for 20 hours. However, the reaction system was heterogeneous, and a polymer was precipitated. The obtained polymer (pO) was insoluble to chloroform, THF, and the like.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH3:18])[CH:3]=1.C[O:20]B(OC)OC.Cl>O1CCCC1.C([Li])CCC.CCCCCC>[CH2:10]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:20])=[CH:3][C:4]=1[CH2:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)cc(C)c1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Yield: 92.9 %

Procedure:
Then, 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene was dissolved in 250 ml of tetrahydrofuran, to which 69 ml of a solution of n-butyl lithium in hexane (1.69 mol/l) was added dropwise with stirring at -70° C. After further stirring at -70° C. for 2 hours, a solution of 12.1 g of trimethoxyboran dissolved in 50 ml of tetrahydrofuran was added dropwise to the reaction solution. After completion of the dropwise addition, the reaction mixture was returned to room temperature and stirred for 1 hour, which was poured into ice water, weakly acidified by the addition of 10% hydrochloric acid and extracted twice with 500 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated. To the residue was added 120 m of toluene, to which 33 ml of 30% aqueous hydrogen peroxide solution was added dropwise with heating at 0° C. under stirring. After heating under reflux for 1 hour, the reaction mixture was returned to room temperature, washed once with water, twice with 10% aqueous ammonium ferrous sulfate solution and further once with water, and the toluene layer was dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.2 g of 4-benzyloxy-3-ethyl-5-methylphenol (yield, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][N:23]([CH3:36])[C:24](=[O:35])[CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:26](=[O:27])[CH:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]([N:23]([CH3:36])[CH3:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(=O)C(C(=O)O)c1ccccc1
Reactant: COc1ccc(NCCc2ccc(OC)c(OC)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(CCc2ccc(OC)c(OC)c2)C(=O)C(C(=O)N(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A mixture of 28.7 mg (0.1 mmol) [2-(3,4-Dimethoxy-phenyl)-ethyl]-(4-methoxy-phenyl)-amine (intermediate 2), 20.7 mg (0.1 mmol) N,N-Dimethyl-2-phenyl-malonamic acid (WO2000009481), 38.5 mg (0.12 mmol) TBTU and 38.7 mg (0.3 mmol) DIPEA in 3 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated diluted with methanol and formic acid and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid, the product containing fractions were evaporated to yield 23.2 mg (61%) of the title compound. MS(m/e): 477.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([CH3:29])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(Cl)c(C)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(C)cc21
Yield: 68.8 %

Procedure:
The title compound was prepared according to General Procedure IV using) 5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.12 g, 0.28 mmol), 20 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2.0 g (11 mmol) of N-bromosuccinimide that was added over 2 h. The product from work-up by General Procedure IV was partially purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 0.5% methanol to give 2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.097 g) of sufficient purity for the next step; 1H NMR (DMSO-d6) δ7.99 (s,1H), 7.66 (s, 1H), 5.93-5.90 (d, 1H, J=8.9 Hz), 5.69-5.62 (m, 3H), 4.02-3.92 (m, 2H), 2.41 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:17])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:18]1(B(O)O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CO>C(COC)OC.O.C(Cl)(Cl)Cl>[CH3:17][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]=2[S:13][C:14]2[C:5]1=[CH:4][CH:3]=[C:2]([C:26]1[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][CH:25]=1)[CH:15]=2
Reactant: CN1c2ccc(Br)cc2Sc2cc(Br)ccc21
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: CN1c2ccc(-c3cccc4ccccc34)cc2Sc2cc(-c3cccc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.30 g (25.1 mmol) of 3,7-dibromo-10-methylphenothiazine, 9.50 g (55.2 mmol) of 1-naphthylboronic acid, 0.407 g (0.50 mmol) of bis(triphenylphosphane)palladium dichloride and 3.80 g (27.5 mmol) of potassium carbonate were heated to boiling under reflux under nitrogen for 5 hours in 204 ml of dimethoxyethane and 101 ml of water. The reaction mixture was cooled to room temperature, stirred further overnight and then filtered. The residue was washed with 470 ml of ethanol and hot water, and dried at 70° C. under reduced pressure. The solid was dissolved in 100 ml of methylene chloride and filtered through silica gel. After the solvent had been removed under reduced pressure, a tacky mass was obtained which, after 200 ml of methanol had been added, crystallized with stirring overnight. The crystals were filtered off with suction, washed with 300 ml of methanol and dried at 40° C. under reduced pressure. 10.33 g of light yellow microcrystals having a melting point of 185-190° C. were obtained. The crude product was recrystallized twice from ethyl acetate. 5.71 g (49% of theory) of analytically pure, almost colorless microcrystals having a melting point of 191-194° C. were obtained, whose solution in chloroform fluoresced at λ=468 nm.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](O)=[O:48].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:25])([CH3:26])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:47](=[O:48])[CH2:46][O:45][C:44]1[C:43]([CH3:42])=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:54])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: Cc1cccc(C)c1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)COc2c(C)cccc2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
EDC-HCl (63 mg) was added to a solution of the compound obtained in Step 2 of Example 17 (127 mg), 2,6-dimethylphenoxyacetic acid (54 mg), and HOBt (41 mg) in DMF, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixture of EtOAc and n-hexane to obtain the title compound (130 mg).