Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccc(F)cc2C1=Nc1ccc2cn[nH]c2c1
Yield: 54.2 %

Procedure:
The title compound (76 mg, 54%) was synthesized as a dark red solid according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol). NMR analysis indicated a 79:21 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H, NH), 11.03 (s, 1H, NH), 8.11 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.22 (dt, J=9.2 Hz, 2.8 Hz, 1H), 6.90 (dd, J=8.4 Hz, 4.4 Hz, 1H), 6.82-6.77 (m, 1H), 5.98 (dd, J=8.0 Hz, 2.0 Hz, 1H); MS ESI 281.0 [M+H]+, calcd for [C15H9FN4O+H]+ 281.1.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:41][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[O:30])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)O)cc2)c2cc(C(C)=O)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a solution of 2-acetyl-7-methoxy-N-(4-carboxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (416 mg, 1.0 mmol), benzenesulfonamide (200 mg, 1.2 mmol), and DMAP (150 mg, 1.2 mmol) in dichloromethane (5 mL) at room temperature was added EDCI (230 mg, 1.2 mmol) in one portion and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (25 mL) and EtOAc (25 mL) and the pH was adjusted to 5–6 with 1.0N HCl. The EtOAc was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 5% to 10% MeOH in EtOAc to give 2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (415 mg). 1H NMR (300 MHz) δ 8.53 (br,1H), 8.46 (br,1H), 8.06 (d,J=7.3 Hz,2H), 7.8–7.3 (m,6H), 7.21 (m,1H), 7.1–7.0 (m,2H), 6.91 (d,J=8.5 Hz,1H), 6.56 (d,J=7.3 Hz,2H), 4.99 (s,2H), 4.02 (s,3H), 2.54 (s,3H).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:21])=[C:15]([NH3+:20])[CH:16]=[N:17]2)=[CH:12][CH:11]=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl>[C:22]([O:25][CH2:26][C:27]([NH:20][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:21])=[CH:12][CH:11]=[C:10]([Br:9])[CH:19]=2)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: [NH3+]c1cnc2cc(Br)ccc2c1O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cnc2cc(Br)ccc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Triethylamine (161 g, 1.59 mol) was added to a suspension of 7-bromo-4-hydroxyquinolin-3-aminium chloride (224 g, 0.815 mol) in dichloromethane (2.25 L), and the mixture was cooled to approximately 0° C. Acetoxyacetyl chloride (112 g, 0.820 mol) was added over a period of one hour. The reaction was stirred at room temperature for one hour and then allowed to stand for three days. A solid was present and was isolated by filtration and pressed dry. The solid was stirred in deionized water (2 L) for two hours, isolated by filtration, dried overnight on the filter funnel, and further dried in a vacuum oven at 60 to 70° C. to provide 223 g of 2-[(7-bromo-4-hydroxyquinolin-3-yl)amino]-2-oxoethyl acetate as a reddish brown solid.
Reaction SMILES: Br[C:2]1(Br)[C:6]2[CH:7]=[N:8][C:9]([Cl:11])=[CH:10][C:5]=2[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]1=[O:20]>C1COCC1.[Cl-].[NH4+].[Zn]>[Cl:11][C:9]1[N:8]=[CH:7][C:6]2[CH2:2][C:3](=[O:20])[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]=2[CH:10]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cnc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Zinc powder (14.8 g, 226 mmol) was added to a biphasic mixture of 3,3-dibromo-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (10.3 g, 22.6 mmol) in THF (129 mL) and saturated ammonium chloride solution (33 mL). Due to delayed exotherm, the reaction was cooled in ice. The reaction was stirred for 3 h at ambient temperature, filtered and the filtrate concentrated. The residue was dissolved in EtOAc (20 mL) and water (20 mL) and passed through a short plug of celite, washing with EtOAc. The organic layer was separated and the aqueous phase extracted with EtOAc (2×20 mL). The combined organic solutions were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel (gradient elution, 0-100%, EtOAc/petrol), gave the title compound (5.08 g, 75%) as a pale yellow oil. 1H NMR (Me-d3-OD): 8.14 (1H, s), 7.18 (1H, s), 5.17 (2H, s), 3.63 (2H, t), 0.94 (2H, t), 0.18-0.18 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:25])CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]2([F:25])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a −78° C. solution of the product of Example 1A (7.13 g, 26.4 mmol) in CH2Cl2 (120 mL) was added diethylaminosulfur trifluoride (DAST, 6.0 g, 4.89 mL, 37.0 mmol). The reaction mixture was allowed to warm to ambient temperature, quenched with water, diluted with ethyl acetate, and washed with water. The organic layer was separated and concentrated. The resulting residue was chromatographed on silica gel, eluting with 0%-30% ethyl acetate-hexane to obtain the title compound (3.0 g, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.69-1.77 (m, 2H), 1.86 (td, J=12.89, 4.75 Hz, 2H), 2.15-2.40 (m, 4H), 3.91 (s, 4H), 7.44 (ddd, J=8.14, 4.75, 0.68 Hz, 1H), 7.96 (dd, J=7.97, 1.53 Hz, 1H), 8.52 (dt, J=4.75, 1.19 Hz, 1H). MS (DCI) m/z 272.05 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][Cl:12])[C:5]([O:7]CC)=[O:6].[OH-].[Na+].S(=O)(=O)(O)O.O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:13][CH2:14][CH2:15][O:16]1)[CH2:11][Cl:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)O)C1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 10.4 g) in ethanol (30 ml) was added an aqueous solution (10 ml) of sodium hydroxide (3.3 g) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was adjusted to pH 7 with 20% sulfuric acid under ice-cooling and stirring, and water (30 ml) was added thereto, and then the solvents are distilled off. To the residue was added water (30 ml), and the resultant solution was washed with diisopropyl ether (50 ml). To the aqueous solution was added diisopropyl ether (100 ml), adjusted to pH 2 with 20% sulfuric acid under ice-cooling and stirring and then saturated with sodium chloride. The diisopropyl ether layer was separated, and the remaining aqueous layer was further extracted with diisopropyl ether. The diisopropyl ether layer and extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with an activated carbon and then filtered. The filtrate was concentrated and the remaining oil was allowed to stand for 1 hour under reduced pressure to give crystals of 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyric acid (syn isomer), mp 80°-81° C. in yield of 99.6%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([O:28][CH3:29])[CH:21]=1.C(=O)([O-])O.[Na+]>>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]4[CH3:18])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: Cc1ccc(C)n1-c1cccc2nc(Cl)n(C)c12
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(Br)cc(C)c1Nc1nc2cccc(-n3c(C)ccc3C)c2n1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A mixture of 90 mg (0.347 mmol) of 2-chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole and 225 mg (1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 110° C. for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 60-90% ethylacetate/n-hexane gradient mixture. The desired fractions were collected and evaporated in vacuo, the residual solids were washed with diethyl ether to give 53.4 mg (35%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([C:18]1[C:13]2[O:12][CH2:11][C@@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:37])[CH3:36]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@H]2c1ccc(C(C)C)cc1
Yield: 46 %

Procedure:
Using N-((3S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 71, the title compound was synthesized in the same manner as in Example 38. Yield: 46%. Melting point: 177-178° C. (hexane-ethyl acetate). [α]D20=−6.0° (c=0.510, chloroform).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])/[CH:23]=[C:24](/[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)\[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:39]>CO>[CH3:25]/[C:24](/[C:26]1[CH:27]=[C:28]([C:32]([NH2:33])=[NH:39])[CH:29]=[CH:30][CH:31]=1)=[CH:23]\[C:22](=[O:34])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CO
Product: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (90 mg, 0.19 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-methyl-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzene-carboxamidine (15 mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+E+): 435.1
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(S(F)(F)[F:29])CC)C.O>ClCCl>[F:29][CH2:21][CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1/C=C/CCCCO
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCc1ccccc1/C=C/CCCCF
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 8.17 g of -(2-nonylphenyl)-1-trans-hexen-6-ol in 20 ml of dichloromethane is added dropwise over a period of 20 minutes to a mixture, cooled with an ice-bath and stirred under an argon atmosphere, of 4.68 g of diethylaminosulphur trifluoride in 20 ml of dichloromethane. After further stirring at room temperature for 14 hours, water is added, and the organic layer is separated off and washed with saturated sodium bicarbonate solution and water. The crude product remaining after the organic phase has been dried and concentrated by evaporation is purified by flash chromatography on silica gel with petroleum ether. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH3:16][C:17]([N+:22]([O-:24])=[O:23])([CH2:20]O)[CH2:18][OH:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[S:9]([O:19][CH2:18][C:17]([CH3:20])([N+:22]([O-:24])=[O:23])[CH2:16][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of triflic anhydride (16.5 ml, 0.1 mol) in chloroform (50 ml) is added a solution of 2-methyl-2-nitro-1,3-propanediol (6.75 g, 0.05 mol) and pyridine (8.85 ml, 0.11 mol) in chloroform (50 ml) with external cooling to ensure a temperature of between 0° and 5° C. during the addition. After the addition the cooling bath is removed and the reaction stirred for 18 hours at ambient temperature. The reaction mixture is transferred to a separating funnel and washed with water. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The crude product is purified by chromatography using a 4:1 mixture of Hexane:Ethyl acetate as eluant; the product is obtained as a solid with melting point 50-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][C:9]=2[N+:24]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:24][C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc([N+](=O)[O-])c2-c2ccc(Br)cc2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2ncc(N)c2-c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-nitro-1H-pyrazole from step2 (2.5 g, 5.7 mmol), iron powder (1.6 g, 28.4 mmol) and NH4Cl (30 mg, 0.57 mmol) in EtOH:H2O (40 mL:10 mL) was refluxed for 1 h. After cooled to room temperature, the mixture was filtered by celite and washed with ethyl acetate and the filtrate was concentrated. Wataer (50 mL) was added to the resiual oil and extracted with ethyl acetate (80 mL), dried over MgSO4, and concentarted in vacuo gave the title compound (1.9 g, 82%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:37])=[C:7]([C:9]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:22]=[N:23][CH:24]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1.[CH2:38]=O.[OH-].[Na+]>C(O)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:37])=[C:7]([C:9]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:22]=[N:23][CH:24]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccc(N4CCNCC4)nc3)c2)c2cccnc2n1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCN(c2ccc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 180 mg (0.34 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(6′-piperazin-1-yl-[3,3′]bipyridinyl-5-yl)-[1,8]naphthyridine hydrochloride in 1.5 ml formic acid was treated with 80 μl (1.01 mmol) 35% aqueous formaldehyde solution and heated to 80° C. The reaction mixture was stirred at this temperature for 2 hours. The volume of the reaction mixture was reduced under vacuum and the residue made strongly alkaline with 2 N NaOH. The resulting precipitate was filtered off, washed with water and dried yielding 2-(5-chloro-2-fluoro-phenyl)-4-[6′-(4-methyl-piperazin-1-yl)-[3,3′]bipyridinyl-5-yl]-[1,8]naphthyridine as gray-green solid; HPLC-MS: 1.55 min, [M+H] 511.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[CH3:32].O>C1COCC1>[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([CH:2]=[O:3])[CH2:36][CH2:35]1)[CH3:32]
Reactant: CN(C)CC1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CCC(C=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (25.7 g, 75 mmole) was suspended in absolute THF (100 ml) under argon, potassium tert-butylate (8.42 g, 75 mmole) dissolved in absolute THF (70 ml) was added dropwise, and then stirred for 15 minutes at 0° C. The corresponding 4-[dimethylaminomethyl]-cyclohexanone 8 (50 mmole), dissolved in absolute THF (75 ml), was then added dropwise to the above solution and stirred overnight at RT. The mixture was hydrolysed by adding dropwise water (38 ml) and 6N HCL 112 ml) while cooling with iced water. After stirring for one hour at RT the mixture was extracted with ether (10×50 ml), the aqueous phase was adjusted to pH 11 with 5N NaOH, shaken with ethyl acetate (3×50 ml), dried over Na2SO4, and concentrated by evaporation in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1). As a rule two diastereomers were obtained in different ratios.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 3-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH2:1]([CH:17]1[CH2:22][C:21](=[O:23])[O:20][C:18]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][NH2:44])=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25]>>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][N:44]2[C:21](=[O:23])[CH2:22][CH:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]2=[O:20])=[O:42])[CH:29]=[C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:33]=1[OH:34])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Product: CCCCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 148 °C
Yield: 102.4 %

Procedure:
2-Hexadecylsuccinic anhydride (10.5 g, 31.3 mmol) was heated to about 115° C. under a nitrogen atmosphere. To this stirred melt was added, in portions, 3-(3,5-di-t-butyl-4hydroxyphenyl)propanoic acid hydrazide (9.2 g, 31.3 mmol). Successive additions of hydrazide required raising the melt temperature to facilitate stirring. The final addition of hydrazide was done at a melt temperature of approximately 135° C. After this final portion was blended into the melt, vacuum was applied and the melt temperature was raised to about 148° C. and maintained at that temperature for 20 minutes. The melt was allowed to cool to approximately 115° C. whereupon the vacuum was released and the clear yellow melt was quickly poured into a container. 19.2 g of a yellow viscous liquid was obtained that solidified to a waxy, translucent white solid upon standing for several days at room temperature. The waxy material was recrystallized from acetone to give a white solid having a melting point of 85° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:13][CH2:14][CH3:15])=[N:9][C:8](=S)[N:7]([CH2:17][CH3:18])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[OH-].[Na+].[Ni]>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][CH2:14][CH3:15])[N:9]=[CH:8][N:7]3[CH2:17][CH3:18])[CH2:3][CH2:2]1
Reactant: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCNc1ncn(CC)c2nc(C3CC3)nc1-2
Temperature: 67.5 °C

Procedure:
The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and 10N NaOH (27 ml) and heated to 65° C. Within 1.25 hours 50% Ni-Al alloy (518 mmoles. of Ni and 1125 mmols of Al) (60.8 g) was added under vigorous stirring at 65-70° C. After a further 0.75 hr at the same temperature the reaction mixture was cooled to room temperature and treated with chloroform (400 ml). The nickel was filtered off and washed with 350 ml of chloroform and 150 ml of water. The filtrate was separated and the chloroform layer evaporated to dryness. The residue (19.64 g) was dissolved in acetone (100 ml), treated with 2 portions of charcoal (0.15 g) filtered and evaporated. The residue was treated with diethylether (100 ml) and crystals collected (6.10 g), mp 80-9° C. A second , crop gave 1.25 g. A recrystallized sample from diisopropylether had mp 103-105° C.