Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])(C)(C)C.CCCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Sn](C)(C)c1cccs1
Temperature: -38 °C
Reaction time: 1 h

Procedure:
To a solution of thiophene (2.1 g, 25.0 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes at −38° C. t-butyllithium in pentane (1.6 M, 16.0 mL, 25.6 mmol). The solution was stirred for 1 h at −38° C. and then cooled to −78° C. Trimethyltin chloride in THF (1 M, 25.3 mL, 25.3 mmol) was added dropwise over 30 min. The reaction was then stirred for 2 h at −78° C. and then for 15 h at r.t. The solvent was evaporated and the resulting yellow solid was taken up in other, washed with water and dried Na2SO4 and then evaporated to give a light brown liquid which solidified on standing.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([I:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:6][CH2:7][C:8]2[CH:15]=[C:14]([I:16])[C:13]([O:17][CH2:21][C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][C:9]=2[CH2:10][CH2:11]1)=[O:4]
Reactant: O=C(N1CCc2cc(O)c(I)cc2CC1)C(F)(F)F
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc2c(cc1I)CCN(C(=O)C(F)(F)F)CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Dry acetone (6 ml) was added to a flask containing the product from step (a) (0.528 g, 1.3 mmol). To this was added 2-Bromo-1-phenyl-ethanone (0.327 g, 1.6 mmol, 1.2 eq) and potassium carbonate (0.378 g, 2.7 mmol, 2.0 eq). The reaction mixture was allowed to stir for 16 hours at room temperature. The acetone was removed under vacuum and the solid was dissolved in dichloromethane, washed with 4N HCl, and brine. Purification by silica-gel chromatography (gradient elution: 0-100% EtOAc in hexanes) gave the sub-title compound as a white solid (552 mg). MS: ESI (positive): 504 (M+H).
Reaction SMILES: [CH2:1]([O:5][C@@H:6]([CH3:12])[C@@H:7]([CH3:11])[C:8](O)=[O:9])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:16])=O>>[CH2:1]([O:5][C@@H:6]([CH3:12])[C@@H:7]([CH3:11])[C:8]([Cl:16])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@H](C)[C@@H](C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCO[C@@H](C)[C@@H](C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.1 g of the (2R,3S)-3-butoxy-2-methylbutyric acid produced in the above i) was added in small portions 5 ml of oxalyl chloride at room temperature. The mixture was stirred for 2 hours at room temperature and then for 30 minutes at 50° C. Excess oxalyl chloride was removed by distillation under reduced pressure. The residue was subjected to Kugel-rohr distillation under reduced pressure to obtain 0.88 g of (2R,3S)-3-butoxy-2-methylbutyric acid chloride.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[NH2:13][OH:14].O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:9]1(=[N:13]/[OH:14])\[CH2:11][CH2:1][CH2:2][C:3]2[C:8]\1=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O/N=C1/CCCc2ccccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of α-tetralone (50 g, 45.5 mL, 342 mmol) in anhydrous methanol (500 mL) was added hydroxylamine hydrochloride (24.7 g, 377 mmol) and sodium carbonate monohydrate (45 g, 363 mmol). The resulting slurry was stirred at ambient temperature for 36 h and the solvent was removed. The residue was titurated with water and the resulting solid was recrystallized from ether/hexanes to supply the product (37.1 g) as greenish tan crystals.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[C:1]([C:4]1[C:5]([O:24][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 25 mL rb flask equipped with a magnetic stir bar was added 0.309 g(0.86 mmol) of the product of Step A, 0.422 g (1.29 mmol) of cesium carbonate, 3 mL DMF and finally 145 μL of 1-bromopinacolone was added. The reaction mixture was stirred at room temperature for 1.5 h then partitioned between EtOAc and water. The organic layer was separated, washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on s silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)C.[C:20]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([N:23]1[CH2:28][CH2:27][C:26]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12

Procedure:
To a solution prepared from 5 g of 2-(2-aminophenyl)indole, 100 ml of ethanol and 2 ml of glacial acetic acid was added dropwise 3 ml of 1-acetyl-4-piperidone. The resultant solution was refluxed for 6 hours and thereafter cooled, whereupon a solid precipitated. Filtration and washing with ether and hexane gave 3.95 g of yellow solid, m.p. 285°-287° dec.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 339 mg (1.79 mmol) 1-bromomethyl-3-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)#[N:2].[Cl:13][C:14]([Cl:29])([Cl:28])[C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:16]>C(#N)C>[Cl:13][C:14]([Cl:28])([Cl:29])[C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16]
Reactant: O=C(Cl)Oc1cccc(NC(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1cccc(NCCC#N)c1
Solvent: CC#N
Product: Cc1cccc(N(CCC#N)C(=O)Oc2cccc(NC(=O)C(Cl)(Cl)Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a solution of 16.0 g N-(2-cyanoethyl)-3-methylaniline in 100 ml acetonitrile, 31.7 g chloroformic acid-3-(trichloromethylcarbonylamino)-phenyl ester taken up in 100 ml acetonitrile is added dropwise. The reaction mixture is heated to boiling for another 10 minutes, cooled, stirred in 500 ml ice water, the precipitate filtered and recrystallized from isopropanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:24])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(C(=O)CCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCN(C(=O)CCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To 3.2 g (13.8 mmol) of 135 in 125 mL of anhydrous methanol was added 21.3 g of ammonium acetate and 20 g of 3A molecular sieves. After stirring 30 min, 3.47 g (55.2 mmol) of sodium cyanoborohydride was added portionwise with stirring. After 3 hours, the mixture was gravity filtered, and the methanol evaporated under vacuum. The residue was partitioned between ice/HCl and ether. The acidic aqueous phase was extracted twice more with ether. The aqueous phase was made basic with ice and 50% aqueous NaOH. The mixture was extracted with CH2Cl2, dried, and evaporated under vacuum to give 1.5 g (47%) of the title amine 136. GC/MS indicated 100% purity with a molecular ion of 232.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:13]([C:27]#[N:28])=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=2)[C:11]=1[C:39]#[N:40].[ClH:41]>C(#N)C.[Cu](Cl)Cl>[Cl:41][C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:13]([C:27]#[N:28])=[C:12]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:33][CH:34]=2)[C:11]=1[C:39]#[N:40]
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
262 mg (2.24 mmol) of isopentyl nitrite and 301 mg (2.24 mmol) of copper(II) chloride were initially charged in 10.4 ml of acetonitrile. 500 mg (1.12 mmol) of the compound from Example 5A were added, and the mixture was then stirred at 60° C. for 4 h. After cooling to RT, 2.2 ml of 1N hydrochloric acid were added. The aqueous phase was extracted three times with in each case 30 ml of ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution, twice with water and once with saturated aqueous sodium chloride solution and dried over sodium sulfate. After removal of the solvent, the product was used without further purification for the subsequent reaction.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[C:30]([C:11](=[O:12])[C:10]4[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2cccc3c2n1C(CN1CCOCC1)CO3
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(C)n3c4c(cccc24)OCC3CN2CCOCC2)cc1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a suspension of 7.5 g (0.056 mole) of aluminum chloride in 100 ml of methylene dichloride (MDC) was added, rapidly with stirring, a solution of 6.2 ml (0.038 mole) of 4-methoxybenzoyl chloride. When addition was complete the mixture was stirred for one hour at room temperature and the resulting solution then added dropwise over a ten minute period with stirring to a solution of 8.5 g (0.031 mole) of 3-(4-morpholinylmethyl)-5-methyl-2,3-dihydropyrrolo-[1,2,3-de]-1,4-benzoxazine in 100 ml of MDC. The resulting mixture was then heated under reflux for thirty minutes, cooled and poured into 300 ml of ice water with stirring. The organic solvent was removed in vacuo, and the residual aqueous medium was diluted with ethyl acetate and neutralized by the addition of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered through silica, taken to dryness in vacuo and chromatographed There was thus obtained about 7 g of crude product which was recrystallized from ethyl acetate/hexane to give 6.0 g of 3-(4-morpholinylmethyl)-5-methyl-6-(4-methoxybenzoyl)-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, m.p. 182°-189° C.
Reaction SMILES: [Na].[CH:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11]>COCCOCCOC.C(OCC)C>[CH3:11][CH2:10][C:9](=[O:12])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: C#CCCCCC
Agent: [Na]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCCCCC#CC(=O)CC
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
A 1-liter reactor was loaded with 345 mL of diglyme (RN 111-96-6) and 17.2 g (748 mmoles) of sodium (RN 7440-23-5) cut into pieces. After heating to a temperature slightly above the melting point of sodium accompanied by thorough stirring, 71.7 g (745 mmoles) i.e. 97.5 mL of 1-heptyne (RN 628-71-7) in solution in 100 mL of diglyme is then added four times at hourly intervals. The medium thickens to form a beige suspension. Stirring is continued for another 2 hours 30 minutes at the same temperature. The mixture is cooled down to 25-30° C. and poured slowly into a stirred solution of 64.8 g (700 mmoles) i.e. 61.0 mL of propionyl chloride (RN 79-03-8) in 600 mL of ethyl ether. An exothermic reaction takes place followed by stirring for 1 hour at no particular temperature.
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+:6].C(O[C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH2:11][CH3:12])C>C(O)C>[C:2]([N-:3][C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH2:11][CH3:12])#[N:1].[Na+:6]
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: N#CN
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC([N-]C#N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In portions, 7.56 g of cyanamide are added to a solution of 32.38 g (33.4 ml, density=0.97 g/l) of 30% sodium methanolate solution and 100 ml of ethanol and the mixture is stirred at 25° C. for ca. 5 minutes; then, over the course of ca. 25 minutes, 30 g (ca. 90% strength, 180 mmol) of (1-ethoxypropylidene)malononitrile are added dropwise. The mixture is stirred for two hours, then the volatile constituents are largely removed by distillation, and the remaining residue is taken up in methylene chloride. The methylene chloride phase is separated off and the remaining 37.57 g of sodium cyano[1-(dicyanomethylidene)propyl]azanide with ca. 80% purity are used in the following stage.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][Cl:10]>>[Cl:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCCBr
Reactant: C1COCCN1
Product: ClCCN1CCOCC1

Procedure:
Morpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 4-(2-chloroethyl)morpholine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH:2]=1.[O:15]1CCC[CH2:16]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[S:13][C:12]([N:14]=[C:16]=[O:15])=[N:11][N:10]=2)[CH:2]=1
Reactant: C1CCOC1
Reactant: Nc1nnc(SCc2cccnc2)s1
Product: O=C=Nc1nnc(SCc2cccnc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 27.7 grams (0.17 mol) of N,N'-carbonyldiimidazole in 200 ml of dry tetrahydrofuran, which mixture was maintained at room temperature under a nitrogen atmosphere, was added a mixture of 17.4 grams(0.078 mol) of 5-[(3-pyridinyl-methyl)thio]-1,3,4-thiadiazol-2-amine (prepared by the method of Example 1) in 300 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour and then at reflux for 15 minutes, followed by cooling to room temperature. The reaction mixture containing the title compound was used in the subsequent reaction without isolation of this isocyanate intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:29][C:25]1[N:26]=[C:27]([NH:1][C:2]2[CH:19]=[C:18]([F:20])[C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[CH:23][N:24]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3c(F)cc(N)cc3F)c12
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
250 mg (0.65 mmol) of 4-(4-amino-2,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 92 mg (0.71 mmol) of 4-chloropyrimidine-2-amine are suspended in 10 ml of water and 5 ml of ethanol. 0.32 ml (1.29 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 2 h. The mixture is made alkaline using concentrated aqueous sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The organic phase is separated off and concentrated. The crude product is purified by preparative HPLC. This gives the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[C:24](O)(=[O:28])[C:25]([CH3:27])=[CH2:26].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: C=C(C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 79.4 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg), methacrylic acid (54.5 mg), 1-ethyl-3-(3-dimethylaminopropyl)-arbodiimide hydrochloride (133 mg) and 1-hydroxybenzotriazole (93.4 mg) in dimethylformamide (4 ml) was stirred for 4.5 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution and brine. The insoluble materials were collected by filtration and recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methacryloylhydrazino)quinoline (190 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.[N:31]1([CH2:36][C:37](O)=[O:38])[CH:35]=[N:34][N:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:37](=[O:38])[CH2:36][N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: O=C(O)Cn1cnnn1
Product: O=C(Cn1cnnn1)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Yield: 48 %

Procedure:
The compound (61 mg, 0.14 mmol) prepared in Example 117 and 1H-tetrazole-1-acetic acid instead of glycolic acid were reacted according to the same procedure as Example 118 to give the title compound (31 mg, Yield 48%).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(c1ccc(O)cc1)c1ccccn1
Reactant: Fc1ncccc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1ccccn1
Temperature: 180 °C

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.4000 g, 2.207 mmol), (4-hydroxyphenyl)(pyridin-2-yl)methanone (0.660 g, 3.31 mmol), and cesium carbonate (2.158 g, 6.62 mmol) in N-Methyl-2-pyrrolidinone (7.36 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 180° C. for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography to give the title compound. MS (ESI, pos. ion) m/z: 361.0 (M+1). IC50 (uM) 0.5561.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>C(Cl)Cl>[S:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[S:16][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)SCCS2
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of ethyl 4-oxocyclohexane carboxylate (5 g, 29.41 mmol) and ethane-1,2-dithiol (4.14 g, 44.11 mmol) in DCM (25 mL) was added BF3.Et2O (4.17 g, 29.41 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a yellow liquid (5.4 g, 75%); 1H NMR (400 MHz, DMSO-d6) δ 4.05 (q, J=7.4 Hz, 2H), 3.34-3.26 (m, 4H), 2.42-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.66-1.54 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:3][N:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccnnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.4 %

Procedure:
To a solution of pyridazine-4-amine (1.73 g, 18.2 mmol) and pyridine (4.41 ml, 54.6 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (3.76 ml, 27.3 mmol) was added, the mixture was stirred for 1.5 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (218 mg, 4.4%) as a solid.