Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1C(=O)CCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: COc1nc(C(C)(C)C)ccc1C=CC(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1nc(C(C)(C)C)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 63 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (17.8 mg, 0.052 mmol) was reacted with 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-acrylic acid (12 mg) DMTMM (1.1 eq, 16 mg) and NMP (1.2 eq, 90 μl) in THF to give the title compound (14 mg, 61.8%) after purification by column chromatography (Hex EtOAc=3/2).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[ClH:20]>CN(C)C=O>[Cl:20][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Reactant: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1Cl)OCc1ccccc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (500 mg) in N,N-dimethylformamide (12.5 mL) was added cuprous chloride (1.62 g), followed by stirring at 140° C. overnight. The reaction mixture was left to be cooled, and then ice water and 1 M hydrochloric acid was added thereto, followed by stirring. After extraction with ethyl acetate, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-hydroxyphenyl)acetate (381 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17](=[O:19])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In a 30 gallon stainless steel unit, 55 L of Dowtherm A (a eutectic mixture of diphenyl and diphenyl ether) was stirred and heated at reflux (253°-257° C.) for one hour. To this was added a solution of 31.3 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate in 10 L Dowtherm A held at 94°-98° C. The addition was effected over a period of four hours so that reflux of the reaction mixture was maintained. The reaction mixture was then allowed to cool and crystallization of the product began. After the temperature had reached 28°-30° C., the solid product was collected on a ceramic filter and washed with 2×9 L dimethylformamide (DMF). The damp filter cake was added to 65 L DMF in a 30 gallon kettle. The resulting slurry was heated at 90°-95° C. for 30 minutes and then cooled to 40° C. The solid was collected on a ceramic filter, washed with 2×8 L DMF and dried at 60° C. for 24 hours to give 23.8 kg ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate containing about 10% of the 5-chloro-6-fluoro isomer as indicated by NMR spectra.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)CCC>C1(C)C=CC=CC=1.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>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(-c3ccco3)ccc2c2c1CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 105.9 %

Procedure:
A suspension of 1.32 g (5.0 mmol) of 7-bromo-1,2,3,5-tetrahydrocyclo-penta[c]quinolin-4-one in 200 mL of toluene is mixed with 1.7 ml (5.5 mmol) of 2-(tributyl-stannyl)furan and 0.29 g (0.25 mmol) of tetrakis(triphenylphosphine)palladium. The reaction mixture is degassed, aerated with nitrogen, stirred for 15 hours at room temperature and heated for 4.5 hours to 110° C. The batch is mixed with silica gel and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 1.33 g of product.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[CH2:15]([C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[S:12][CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(Cc2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(Cc2ccccc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-benzyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 32, Part E). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([CH:10]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]>C1C=CC=CC=1>[CH2:5]([CH:10]1[CH2:13][CH:12]([C:14]([Cl:3])=[O:16])[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC1CC(C(=O)O)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC1CC(C(=O)Cl)C1
Yield: 91.1 %

Procedure:
A reaction vessel was charged with 140 g of thionyl chloride and 100 ml of benzene, and 100 g of 3-pentylcyclobutanecarboxylic acid was added dropwise under reflux with stirring. The resultant mixture was refluxed with stirring for 8 hours and the excess thionyl chloride was azeotropically distilled off with benzene and the residue was distilled under reduced pressure to obtain 101 g (yield 91%) of 3-pentylcyclobutanecarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:20][C:16]3([CH3:15])[CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Reactant: CC1(N)CCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.3 g, 5.3 mmol), 1-methylcyclobutylamine hydrochloride (1.0 g, 8.1 mmol) and triethylamine (2.5 ml, 18.1 mmol) in ethanol (10 ml) was stirred for 16 h at 50° C. and then for 5 h at 70° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water (25 ml) followed by adjustment to pH <2 with 1M hydrochloric acid. The crude product was isolated by filtration, recrystallised from acetic acid and finally purified by chromatography (C18; 20-60% acetonitrile+0.01% TFA) to give 363 mg (22%) of the title compound; mp 294-296° C.; 1H-NMR (DMSO-d6): δ1.48 (s, 3H), 1.75-1.88 (m, 2H), 1.94-2.05 (m, 2H), 2.18-2.31 (m, 2H), 7.08 (s, 1H) 7.33 (br s, 1H), 10.67 (br s, 1H); LC-MS: m/e 306/308 (M+1)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>CC1C=CC(C)=CC=1>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: C=C(C)c1cccc(C(=C)C)c1
Reactant: Oc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
A 500-ml three-neck reactor was charged with Amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and p-xylene (60 ml). The contents were heated up to 80° C. in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and p-xylene (60 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid chromatography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,3-diisopropylbenzene, 30.5 g, yield 93%), the intended product, and the o, p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 1.67 g, yield 5.1%), were obtained.
Reaction SMILES: NC1C=CC(OC)=[C:6]([OH:8])C=1.C[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:6][O:8][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(N)cc1O
Reactant: CC(=O)Nc1ccc(C)c(OCCOc2ccccc2)c1
Product: COc1ccc(NC(C)=O)cc1OCCOc1ccccc1
Yield: 62 %

Procedure:
The compound 19a was prepared starting from 5-amino-2-methoxy phenol (800 mg, 5.75 mmol) according to the procedure described for the synthesis of 18a (as in Example 27) in 62% yield as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[C@H:9]([C:11]([O:13]C)=[O:12])[CH3:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.O.[OH-].[Li+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:16])=[O:17])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1
Reactant: COC(=O)[C@H](C)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2Cc2c(F)cccc2F)[C@@H](C)C(=O)O)cc1OC
Reaction time: 18 h
Yield: 36.9 %

Procedure:
To 1.373 g of methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]alaninate dissolved in 20 ml of ethanol is added 0.52 g of lithium hydroxide monohydrate, and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is taken up in ethyl acetate and washed with 5% potassium hydrogen sulfate solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) dichloromethane/methanol mixture to give 0.494 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Br)[C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:12]#[N:13])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Cl)ccnc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(Cl)ccnc1CC#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Chloro-3-methoxy-2-bromomethyl-pyridine (4.69 g) and sodium cyanide (5.11 g) are added to ml of a 1/1 mixture of water and ethanol. The reaction is stirred at 60° C. for 3 hours. The ethanol is evaporated and the residue diluted in water and extracted with methylene chloride. The desired product is obtained by chromatography using hexane/ethyl acetate (9/1) as solvent.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:39]1([CH2:45][CH2:46][CH2:47]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:47][CH2:46][CH2:45][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: ClCCCN1CCCCC1
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCN2CCCCC2)CC1
Temperature: 100 °C

Procedure:
In a 25 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (69.9 mg, 0.13 mmol), potassium carbonate (161.9 mg, 1.17 mmol), potassium iodide (21.6 mg, 0.13 mmol), 3-(piperidin-1-yl)propyl chloride (33.52 mg, 0.17 mmol) and N,N-dimethylformamide (3 ml). The resulting mixture was heated to 100° C. and maintained at this temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl>C1COCC1.CO.[Fe]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.900 g, 2.9 mmol) in THF was added methanol (53 ml, 1297 mmol) and 1N HCl (8.6 ml, 8.6 mmol). The resulting mixture was cooled to 0° C. Iron (2.2 g, 40 mmol) was added, and the reaction was allowed to stir at RT for 3.5 hours. The reaction mixture was then diluted with MeOH, filtered through a pad of Celite, and concentrated in vacuo. The residue was then diluted with sat. NaHCO3 (aq) and CH2Cl2. The aqueous layer was separated and extracted three times with CH2Cl2. The combined organic extracts were dried over sodium sulfate and filtered through a pad of silica gel using 10% MeOH/CH2Cl2. The collected fractions were concentrated in vacuo and purified by silica gel chromatography (80 g column; 2% MeOH/CH2Cl2 for 10 minutes then 3.5% MeOH/CH2Cl2 for 10 minutes). Fractions containing pure product were concentrated to yield 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine as a tan solid. Calcd for C16H13FN2O2: [M]+=284. Found: [M+H]+=285.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccccn1)NO
Reaction time: 72 h
Yield: 85 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (524 mg, 1.60 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 then 100:8) to furnish III as a colourless oil (425.79 mg, 85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1N
Solvent: CO
Solvent: O
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(C)CCON
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 in dehydrated methylene chloride (10 mL) was cooled to 0° C. under an argon atmosphere, followed by adding dropwise isobutyl chloroformate (289 μL, 2.20 mmol). Then, triethylamine (293 μL) was added, followed by stirring for 30 minutes. Thereby, a mixed acid anhydride was prepared in the reaction system. To this reaction mixture were gradually added 2-(aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) described in Reference Example 18 and triethylamine (930 μL) while washing with dehydrated methylene chloride (7.0 mL), followed by stirring at the same temperature for 1 hour. This reaction mixture was filtered though Kiriyama filter paper. Subsequently, the residue was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride and water, and the organic layer extracted with methylene chloride was dried over magnesium sulfate, followed by distilling off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (amino silica, chloroform/methanol=10/1) to afford 291.1 mg of the title compound as a colorless oil (yield 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[K+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([N:8]2[C:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=3)=[N:10][NH:11][C:28]2=[O:29])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n[nH]c1=O
Temperature: 24 °C
Reaction time: 18 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzene carbohydrazonamide (4 g, 9.7 mmol) was taken up in THF (600 ml) under N2, and 1,1'-carbonyldiimidazole (1.9 g, 11.72 mmol) added. The solution was stirred for 18 h at 24° C. before solvent was removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 2.92 g (68.6%) mp 205.5°-207° C. IR(KBr, ν=cm-1) 3170, 3057, 1726,1504, 1277, 1128; 1H NMR (300 MHz, DMSO-d6) δ3.48 (3H, s), 7.15 (1H, d, J=9.0 Hz), 7.55 (1H, dd, J=8.9 Hz, 2.6 Hz), 7.69 (1H, d, J=2.6 Hz), 7.87 (2H, br.s), 8.17 (1H, br.s), 12.50 (1H, br.s); MS(DCl)m/z: 438(MH+). Anal. calcd. for C17H10ClF6N3O2 : C, 46.65; H, 2.30; N, 9.60. Found: C, 46.71; H, 2.20; N, 9.60.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31].[Cl-].[Li+]>O1CCOCC1.O.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>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([NH2:9])=[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)[C:2]=1[CH:30]=[CH2:31]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cnc(Cl)c(Br)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(Cl)ncc(N)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (93 mg, 0.19 mmol), vinyltributyl tin (63 μL, 0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %) and lithium chloride (25 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layer was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 4 g column, ISCO, 0-10% MeOH in DCM) to afford the title compound as a beige powder (77 mg, 82%). 1H NMR (CDCl3, 400 MHz): 8.50 (dd, J=2.5, 1.0 Hz, 1H), 7.94 (s, 1H), 7.88 (dd, J=8.5, 2.5 Hz, 1H), 7.54-7.47 (m, 4H), 6.53 (dd, J=18.0, 11.5 Hz, 1H), 5.37 (dd, J=11.5, 1.0 Hz, 1H), 5.11 (dd, J=18.0, 1.0 Hz, 1H), 3.60 (s, 2H), 3.55-3.50 (m, 2H), 2.48-2.35 (m, 4H), 1.68-1.58 (m, 4H), 1.50-1.44 (m, 2H). LCMS (Method B): RT=2.32 min, M+H+=423/425.