Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][C@H:11]([CH3:21])[C:12]3[C@:17]2([CH3:19])[CH:16]=[CH:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:27])([C@@:5]([OH:26])([C:22](=[O:25])[CH2:23][OH:24])[CH2:6][CH2:7]2)[CH2:3]1.[H][H]>CCOC(C)=O.C(O)C>[OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][C@H:11]([CH3:21])[C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:27])([C@@:5]([OH:26])([C:22](=[O:25])[CH2:23][OH:24])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Yield: 94.2 %

Procedure:
In a 250 mL round-bottomed flask was suspended (6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (6α-Methyl-Prednisolone, 4.3 g, 11.48 mmol) in EtOAc (80 mL) and the reaction mixture was diluted with ethanol (20.0 mL). Wilkinsons catalyst (1 g, 1.08 mmol) was added and the mixture was hydrogenated for 1 week whilst stirring at room temperature in a hydrogen atmosphere (1 atm). The mixture was filtered and the filtrate was concentrated in vacuo, giving 4.07 g of a light brown solid. The material was used as such without any further purification. APCI-MS m/z: 377 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].Cl[CH2:9][C:10]([O-:12])=[O:11].[Na+].O>CCCCCC.C1COCC1.CS(C)=O>[CH3:3][CH:4]([CH3:7])[CH2:5][O:6][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)CO
Reactant: O=C([O-])CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)COCC(=O)O
Temperature: -15 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
Sodium hydride (1.72 g of 60% NaH in oil=1.03 g, 43 mmol) in oil dispersion was washed twice with 10 ml of hexane. THF was added (10 ml) and the mixture was cooled to -15° C. A solution of 2-methyl propanol (2.5 g, 35 mmol) in THF was then added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum and a solution of sodium chloroacetate (5.2 g, 45 mmol) in DMSO (100 ml) was added. The mixture was stirred at room temperature for 20 hours, then diluted with 300 ml. of water. The mixture was extracted twice with 50 ml. of hexane. The agueous phase was acidified with 4 N hydrochloric acid and the product was extracted twice with 100 ml. of ethyl acetate. The combined ethyl acetate layers were washed twice with 100 ml. water, dried over MgSO4, filtered, and the solvent was removed by distillation under reduced pressure to give 4.6g of product as a colorless oil. Yield of product=99.6%.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.[Br:15][CH2:16][CH2:17]Br.C(OCC)(=O)C>CS(C)=O>[Br:15][CH2:16][CH2:17][N:6]([N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)[C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium-hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromoethane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61, (t, J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 292.0 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:40]=[CH:39][C:16]2[NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[O:22])=[N:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl.C(OC(C)C)(C)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:40]=[CH:39][C:16]2[NH:17][C:18]([NH:20][C:21](=[O:22])[NH:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[N:19][C:15]=2[CH:14]=1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNC(=O)Nc2nc3cc(OS(=O)(=O)c4c(Cl)cccc4Cl)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(NCCN1CCNCC1)Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of 340 mg of tert-butyl 4-(2-{[(5-{[(2,6-dichlorophenyl)sulfonyl]oxy}-1H-benzimidazol-2-yl)carbamoyl]amino}ethyl)-piperazine-1-carboxylate in 60 cm3 of dichloromethane are added 631 mg of trifluoroacetic acid. The mixture is stirred for 24 hours at a temperature in the region of 20° C., and 590 mg of trifluoroacetic acid are then added. The reaction medium is stirred for three days and then evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 25 cm3 of water, brought to pH 9 with potassium carbonate and then extracted with three times 50 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). After flash chromatography on a column of silica [eluent: chloroform/methanol/28% aqueous ammonia (12/6/0.5 by volume)], the resin obtained is solidified in 25 cm3 of diisopropyl ether, filtered, washed with three times 2 cm3 of diisopropyl ether and then dried under reduced pressure over phosphorus pentoxide. 165 mg of 2-{[(2-piperazin-1-ylethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20](I)[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C.[Cu]I>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20]([O:2][CH3:1])[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(I)cc2n1Cc1ccccc1
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(cc1F)c(C(=O)NCc1ccc(F)c(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 110 °C

Procedure:
To a mixture of sodium methoxide (freshly prepared from 25 mg sodium and 1 ml MeOH) and CuI (30 mg, 0.16 mmol) was added a solution of 1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-6-iodo-2-isopropyl-1H-indole-3-carboxamide (Compound 179, 30 mg, 0.053 mmol) in DMF (0.5 ml). The reaction was heated to 110 ° C. for 16 h, and was filtered and concentrated. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccco1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccco1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 247 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:23].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:83]1[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]1)(OC(C)(C)C)=O.Cl>C1(C)C=CC=CC=1.CO.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N:6]1[C:5](=[O:23])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:83]3[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]3)[CH:3]=2)[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCNCC4)cc3c2=O)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (2 g), Cs2CO3 (4.4 g), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.67 g), palladium acetate (0.12 g) in anhydrous toluene (20 ml) at ambient temperature was added N-boc piperazine (2.5 g). The mixture was heated to 100° C. and stirred for 16 hours. Inorganic solids were removed via a hot filtration and the filtrate concentrated to give an oil. The oil was resuspended in MeOH (16 ml), 4N HCl in dioxane (10 ml) was added and the reaction mixture stirred at 50° C. for 1 hour when additional 4N HCl in dioxane (2 ml) was added and heating continued for a further 30 minutes. The reaction mixture was cooled to room temperature and the solid collected by filteration, washed with ethyl acetate (×2) and ether and dried. The resultant solid was suspended in saturated K2CO3 solution and extracted with ethyl acetate (×5). The organic layers combined, dried (magnesium sulphate) and concentrated to yield methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate as a yellow foam (1.41 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.31 (m, 1H), 2.87 (m, 4H), 3.19 (m, 4H), 3.87 (s, 3H), 7.46 (s, 1H), 7.61 (m, 3H), 7.97 (s, 1H), 8.02 (d, 1H), 8.08 (s, 1H); Mass Spectrum: M+H+ 379.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([OH:18])[C:14]([CH3:19])=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:15]2[C:14]([CH3:19])=[N:13][N:12]([CH3:11])[C:16]=2[CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1nn(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)c(C)c1Oc1ccc(Br)cc1C=O
Yield: 100.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluoro-benzaldehyde (2 g, 10 mmol) (Acros) was reacted with 1,3,5-trimethyl-1H-pyrazol-4-ol (1.3 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-benzaldehyde as a white solid (Yield 3.1 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].C(NCC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]([CH2:20][CH3:19])[CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Solvent: CCO
Solvent: CCNCC
Product: CCOC(=O)c1c(N(CC)CC)c2ccc(C)nc2n(CC)c1=O
Reaction time: 16 h

Procedure:
A mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 0.7 g. (0.01 mole) of diethylamine in 20 ml. of ethanol was heated in an autoclave placed in a steam bath for 16 hours. The solution was then evaporated in a rotary evaporator and the residue was triturated with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated in a rotary evaporator. The residue was recrystallized from heptane. A second recrystallization from petroleum ether gave 0.4 g. of product, m.p. 79°-82° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[I-].[Na+]>[Cl-].[Na+].O>[Si:19]([O:18][CH2:17][CH2:16][N:9]1[C:10]2[C:5](=[C:4]([F:3])[CH:13]=[CH:12][CH:11]=2)[NH:6][CH2:7][C:8]1=[O:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60%, 128 mg, 3.2 mmol) was added to a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (530 mg, 3.2 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 10 min. (2-Bromoethoxy)-tert-butyldimethylsilane (789 mg, 3.3 mmol) and sodium iodide (495 mg, 3.3 mmol) were added and the mixture was stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was taken up in EtOAc and brine, separated and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet.ether 40:60) to give a pale yellow solid: yield 600 mg, 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of 2-chloro-4-nitrophenol (2.761 g), chloromethyl methyl ether (2.4 mL), acetone (16 mL) and potassium carbonate (3.1 g) was heated under reflux for 5 hours. The reaction mixture was poured in saturated saline solution, and the product was extracted with diethyl ether. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off, to provide crude 2-chloro-1-methoxy-methoxy-4-nitrobenzene (3.091 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C(O)C>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
2-Mercaptobenzimidazole (4.73 g) was dissolved in 150 ml of ethanol, and to the solution was added 6.18 g of 2-dimethylaminobenzyl chloride hydrochloride. The mixture was stirred at room temperature for 30 minutes. Precipitated crystals were collected by filtration. A saturated aqueous NaHCO3 solution was added to the crystals, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and acetonitrile to obtain 5.39 g of 2-(2-dimethylaminobenzylthio)benzimidazole as a colorless crystalline product (m.p. 164° C.).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11]([CH:13]([N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66].CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11]([CH:13]([N:24]([CH3:34])[C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])=[O:30])=[CH:32][CH:33]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:12]
Reactant: NCCS(=O)(=O)O
Reactant: CN(c1ccc(C(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(C(=O)NCCS(=O)(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
4-{[(4-Benzofuran-2-yl-phenylcarbamoyl)-(4-tert-butyl-phenyl)-methyl]-methyl-amino}-benzoic acid (110 mg, 0.2 mmol), was taken up in 3 mL of DMF followed by addition of HOBt (79 mg, 0.52 mmol) and EDCI (99 mg, 0.52 mmol). The reaction was stirred at RT for 30 min, taurine (103 mg, 0.083 mmol) was added followed by Hunig's base (107 mg, 0.083 mmol) and allowed to stir an additional 16 h at RT. The solution was filtered through a fit and the DMF was subjected to reverse phase HPLC purification. After removal acetonitrile/water under reduced pressure, followed by trituration with methanol, gave a white solid (50 mg, 39%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[N:8][C:7]=1[NH:13][NH2:14])[C:2](=[CH2:4])[CH3:3].[OH-].[Na+].[H][H]>CO.[Pd]>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[NH:13][NH2:14])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C)CNc1cc(Cl)nnc1NN
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CNc1ccnnc1NN
Reaction time: 4 h

Procedure:
A solution of 4.0 of 4-methallylamino-6-chloro-3-hydrazinopyridazine in 150 ml. of methanol and 50 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solution 2.0 g. of 10% palladium on carbon is added. The Paar shaker is charged with hydrogen at room temperature to an initial pressure of 50 psi and shaken. After about 4 hours, the reaction mixture is filtered, the solvent evaporated and the residue extracted with chloroform. The chloroform is evaporated off and the 4-isobutylamino-3-hydrazinopyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the product, 4-isobutylamino-3-hydrazinopyridazine hydrochloride (m.p. 211°-212°C.) which precipitates, is collected by filtration.
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[N:47]1([CH2:52][C@@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:52][C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3CN3CCCC3)n2)c1

Procedure:
B32 was prepared following the procedure reported for B4 using A1 and (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and obtained as a white crystalline solid; yield: 87 mg (23%). MS (ES) C19H27N7O2S requires: 417. found: 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl:17]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene under protective gas are added 51.8 g of potassium carbonate. Subsequently, while illuminating with a mercury lamp, 24 g of chlorine gas are introduced at 20° C. within 4 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 20° C. for a further 20 minutes. The solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: COc1ccc(Cl)cc1NC(=O)C1CCNCC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-(piperidine-4-carboxamido)anisole (10.4 g) was dissolved in a mixture of acetic acid (100 ml) and concentrated sulphuric acid (5 ml). Fuming nitric acid (2.1 ml) was added dropwise, keeping the temperature below 30°. The solution was stirred at room temperature for 2 hr, poured onto crushed ice (ca 500 ml) and basified with 40% sodium hydroxide. The mixture was extracted with ethyl acetate (2×250 ml), the extracts dried (K2CO3) and solvent removed at the pump. The brown residue was crystallised from ethyl acetate and petroleum ether (b.p. 60°-80°), giving 4-chloro-5-nitro-2-(piperidine-4-carboxamido)anisole as brown plates (e17) (9.9 g, 82%), m.p. 167°-170°.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[O:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Oc2ncnc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(Oc2ncnc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-amine (Intermediate-10, 100 mg, 0.369 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 211 mg, 0.738 mmol), oxalyl chloride (139 mg, 1.11 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) in CH2Cl2 (5 mL) to afford 8 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.81-8.62 (m, 2H), 8.16 (br t, 1H), 7.95-7.92 (d, J=8.4 Hz, 1H), 7.74-7.69 (t, J=8.4 Hz, 1H), 7.41-7.30 (m, 2H), 5.37 (m, 1H), 4.31-4.30 (d, J=5.4 Hz, 2H), 1.94 (m, 2H), 1.82-1.78 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.14 (s, 9H), 1.00 (s, 3H), 0.67 (s, 3H); MS (m/z): 541.14 (M+H)+.