Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[NH2:45][CH2:46][C:47]([NH2:49])=[O:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7](Cl)=[O:8].[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([N:34]=[N+]=[N-])[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]>CN(C)C=O.N1C=CC=CC=1>[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([NH:34][C:7](=[O:8])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=3)[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reactant: O=C(Cl)C=Cc1ccc(O)c(O)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccc(O)c(O)c1)N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 1.5 h

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39]>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH3:39])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(N)c3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cccc(C#Cc2ccc3c(=NOC(C)(C)C)cc(-c4cc5ccccc5cn4)oc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 7-(3-aminophenylethynyl)-2-(Isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 29) (127 mg, 0.286 mmol) in dimethylformamide (3 ml) was added to a cold suspension of sodium hydride (60% in mineral oil, 24 mg, 0.608 mmol) in DMF (1 ml). The reaction mixture was stirred for 1 hour at room temperature and cooled to 0° C. Iodomethane (43 μl, 0.690 mmol) was added and the solution was stirred at room temperature for 18 hours. The mixture was poured onto water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-45%) to yield 2-Isoquinolin-3-yl-7-{3-methylaminophenylethynyl}-chromen-4-one O-tert-butyl oxime (65 mg, 50%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:23]2[CH:24]=[CH:25][NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2[nH]cc(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.45 g, 2.2 mmol) and potassium carbonate (0.35 g, 2.5 mmol). The product was isolated as a white foam. Yield 220 mg (25%). mp 198°-202° C. FDMS m/e=406 (M+ of free base).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:4]2)=[CH:11][CH:12]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(Cc2ccc(F)cc2)CCO1)Nc1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of 2-aminomethyl-4-(p-fluorobenzyl)-morpholine (1.0 g, 4.5 mmol) in dimethylformamide (10 ml) was added under ice-cooling phenyl isocyanate (0.53 ml, 4.9 mmol) and the mixture was stirred for 30 minutes. To the reaction mixture was added purified water (20 ml) and the crystals thus separated out were then recovered by filtration to give the title compound (1.1 g). Yield=72%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(C#N)(C)=O.[Na+].[I-].Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)C#N
Agent: [I-]
Agent: [Na+]
Product: C[Si](C)(C)OC1=CCCc2cc(O[Si](C)(C)C)ccc21
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 6-hydroxytetralone (0.972 g, 6.0 mmol) in 10 mL of freshly distilled AcCN at room temperature was added sequentially dry NaI (2.25 g, 15 mmol), TEA (2.10 mL, 15 mmol), and chlorotrimethylsilane (1.92 mL, 15 mmol). After stirring for 1 hour, the reaction was quenched with the addition of a cold solution of saturated ammonium chloride and the reaction was extracted into Et2O (2×100 mL). The combined extracts were washed with ice cold water and then dried, filtered, and concentrated in vacuo to afford 1.53 g of the title compound as a colorless oil which was used for further reaction without purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[CH:3][CH:2]=1.ClN1C(=O)C[CH2:12][C:11]1=[O:16].[SH:17]C(O)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[C:4]1([CH2:7][S:8][S:17][CH2:12][CH2:11][OH:16])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(O)S
Reactant: O=C1CCC(=O)N1Cl
Reactant: SCc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCSSCc1ccccc1
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A solution of benzylthiol (1.17 ml) in dry toluene (2 ml) was added dropwise over 5 min to a suspension of N-chlorosuccinimide (1.34 g) in toluene (5 ml). The mixture was stirred for 5 min the a mixture of mercaptoethanol (700 μl) and triethylamine (1.34 ml) in toluene (3 ml) was added dropwise over 5 min. The mixture was stirred for a further 10 min the diluted to 30 ml with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with dichloromethane to afford the title compound (522 mg, 25%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([CH:22]4[CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.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:22]1([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:29]5[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)[CH2:24][CH2:23]1
Reactant: Cc1nc(-n2nc(C3CC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: CC#N
Product: Cc1nc(-n2nc(C3CC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 70.6 %

Procedure:
A suspension of 1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5(4H)-one (0.285 g, 0.829 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), Cs2CO3 (0.600 g, 1.842 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in MeCN (20 mL) was heated at 100° C. under argon for 4 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2×20 mL). The combined organics were dried, concentrated, and purified by silica gel chromatography (0-20% MeOH/DCM) to provide 3-cyclopropyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.228 g, 66%) as a white solid. 1H NMR (400 MHz, dmso): δ 11.80 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.32 (s, 3H), 1.87 (tt, J=8.4, 5.1 Hz, 1H), 0.95 (m, 4H); MS (ESI) m/z: 390.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].O.[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[CH:12][NH:13][C:14](=[NH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([O-])=O>[Pd].CO>[NH2:4][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[CH:12][NH:13][C:14](=[NH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: N=C(NC=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(NC=Cc1ccc(N)cc1)c1ccccc1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A nitrogen atmosphere is employed throughout the reaction. A solution of sodium borohydride (3.8 g., 0.1 mole) in 10 ml. of water is added to a suspension of about 200 mg. of 10% palladium on carbon in 10 ml. of water. After 5 min., 200 ml. of methanol is added followed by portion-wise addition of finely powdered N-(4-nitrostyryl)benzamidine (8.0 g., 0.03 mole) over a period of 5 min. During the addition, the mixture refluxes and continues to boil for about 5-10 min. thereafter. The reaction mixture is stirred without external heating for 0.5 hr., filtered through celite, concentrated under reduced pressure and the residue stirred with 25 ml. of water and filtered. The filter cake washed with cold water, dried, and triturated with isopropyl alcohol provides 6.8 g. (86% yield) of N-(4-aminostyryl)benzamidine free base, m.p. 166°-168° C. Treating the free base in methanol with ethanolic hydrogen chloride and evaporating the solvent under reduced pressure provides the crude hydrochloride. Analytically pure N-(4-AMINOSTYRYL)BENZAMIDINE DIHYDROCHLORIDE, m.p. 217.5°-219.5° C. (dec.)(corr.), (60% yield) is obtained by first triturating the crude hydrochloride with acetone and then recrystallizing from methanol-isopropyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A stirred solution of 15.3 grams (0.077 mole) of (4-(2-pyridyloxy)phenyl)formaldehyde (a known compound) in 150 mL of methanol was cooled to 0-5° C., and 3.2 grams (0.085 mole) of sodium borohydride was added portion wise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, the reaction mixture was cooled to 5° C. and 150 mL of water was carefully added to destroy excess sodium borohydride. The mixture was cooled to 0° C. and neutralized with concentrated hydrochloric acid. Excess acid was added causing the mixture to be acidic. The mixture was brought to neutrality by the addition of solid sodium bicarbonate. The mixture was concentrated under reduced pressure to remove some of the methanol. The concentrate was taken up in ethyl acetate and washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 12.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:27]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([S:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH3:27])(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Nc1cccc(CO)c1)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc(CO)c1)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reaction time: 3 h

Procedure:
2′,4′-Dichlorobiphenyl-4-sulfonic acid-(3-hydroxymethyl-phenyl)-amide (ABD455) (0.4 g) was dissolved in DMF (20 ml). K2CO3 (1 g) was added followed by methyl iodide (1 ml). The mixture was stirred vigorously for 3 hrs, poured into water and extracted with ether. After drying (Na2SO4), the solvent was partially removed under vacuum and petrol added to induce crystallisation and the product collected as white crystals. 13C NMR (CDCl3): δ 38.4, 64.7, 125.3, 125.7, 126.0, 127.5, 127.7, 129.2, 129.8, 130.1, 131.9, 133.1, 134.9, 135.8, 137.2, 141.6, 142.0 and 142.8. 1H NMR (CDCl3): δ 3.22 (3H, s), 4.65 (2H, d, J=5.8 Hz), 7.02 (1H, m), 7.14 (1H, s), 7.28 (1H, s), 7.30 (3H, m), 7.48 (2H, d, J=8.2 Hz), 7.50 (1H, m) and 7.60 (2H, d, J=8.2 Hz).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([NH:26][C:27]1[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[CH2:19]([N:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]=[C:15]1[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3n2Cc2ccccc2)[nH]1
Yield: 54.2 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 455 mg of N-benzylbenzene-1,2-diamine and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2.5 ml of pyridine and 2.5 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for forty-five minutes and purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, 250 mg of 2-[(1-benzyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a cream powder, the characteristics of which are the following:
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CO.[CH3:32][Si](C=[N+]=[N-])(C)C>O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[N:24]([CH3:32])[C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-adamantan-1-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide (66 mg, 0.159 mmol) in dioxane (1.5 ml) was added methanol (0.32 ml) followed by a 2.0 M solution of (trimethylsilyl)diazomethane (0.32 ml). After stirring for 18 hours at ambient temperature the mixture was concentrated under reduced pressure to give 67 mg of a light yellow amorphous solid. Mass Specrum (ES+) 429.6; (ES−) 427.6. Liquid chromatography retention time=2.8 min (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:10]1[N:11](C(=O)C)[CH2:12][C:13]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]=2[N:15]=1.[OH-].[Na+]>CO>[NH2:8][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[NH:11][CH2:12][C:13]3[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:14]=3[N:15]=2)[CH2:4][CH2:3]1
Reactant: CC1(N)CCNCC1
Reactant: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(N)CCN(C2=Nc3c(nc(Cl)nc3Nc3ccc(F)c(Cl)c3)CN2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At 60° C. a mixture of 30.8 g (0.270 mol) of 4-methylpiperidin-4-ylamine and 100 ml of methanol is added dropwise to a suspension of 100 g (0.257 mol) of (3) in 690 ml of methanol. The mixture is stirred for 1 hour at 60° C., allowed to cool to 40° C., 280 ml of 2N sodium hydroxide solution are added and the resulting mixture is stirred for 3 hours at 60° C. Then 300 ml of methanol are distilled off and 600 ml of water are added. The mixture is stirred for 5 minutes at ambient temperature, filtered off and the residue is washed with 250 ml of water, 3 times 50 ml of acetone and 100 ml of methyl-tert-butylether and dried at 40° C. in vacuo. Yield: 100.5 g (92.2%), melting point 211.5° C. 400 MHz-1H-NMR (DMSO) (ppm)=8.55 br s, 1H, NH; 8.05 dd, 1H, aniline-H; 7.78 ddd, 1H, aniline-H; 7.47 t, 1H, aniline-H; 6.90 br s, 1H, NH; 4.28 s, 2H, CH2; 3.68 m, 2H, CH2; 3.45 m, 2H, CH2, 3.32 br s, 2H, NH2; 1.37 m, 4H, 2CH2; 1.05 s, 3H, CH3.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([NH2:30])=[CH:25][C:24]=2[CH3:31])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N:30]=[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][NH:6]3)=[CH:25][C:24]=2[CH3:31])=[CH:21][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCCCN1
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N=C1CCCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 0.2 g (1.5 mmol) of phosphoric trichloride in 5 ml toluene was added to a mixture of 0.3 g (3.0 mmol) of piperidin-2-one, the exothermic reaction was stirred for 2 hrs at ambient temperature. Then a solution of 0.38 g (1.5 mmol) of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine in 5 ml of toluene was added and the reaction mixture was refluxed for 5 hrs. At ambient temperature 5 ml of a 10% aqueous solution of sodium hydroxide was added. Separation of the layers, extraction of the watery layer with 10 ml of toluene, drying over magnesium sulfate, concentration in vacuo and column chromatographic (gradient: cyclohexane->ethyl acetate) yielded 0.3 g (1.0 mmol) 63% of 4′-tert-butyl-2,5-dimethyl-N-[piperidin-2-ylidene]biphenyl-4-amine; log P (pH 2.3)=2.6.