Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[Cl:2][C:3]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Br:17][C:18]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([Br:28])[C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Br:17][C:18]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([Br:28])[C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Cl:2])[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C(Cl)c1c(Br)cc(Br)cc1Br
Reactant: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1c(Br)cc(Br)cc1Br)N1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrachlorophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Tribromobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,4,6-tribromobenzoyl)-3,4,5,6-tetrachlorophthalimide.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21](=[S:23])[NH2:22])[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]3[S:23][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:22]=3)[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=S)nc2c1C#N
Reactant: CCOC(=O)C(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Temperature: 125 °C
Yield: 91.3 %

Procedure:
Ethyl 3-bromopyruvate (72.2 μl, 0.518 mmol) was added to a toluene (10 ml) solution of 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carbothioamide (I-196-1) (124 mg, 0.398 mmol), followed by heating under reflux in an oil bath at 125° C. for 2 hours. After cooling to room temperature, p-toluenesulfonic acid monohydrate (15.2 mg, 0.080 mmol) was added to the reaction liquid, followed by heating under reflux in an oil bath at 125° C. for 15 hours. After cooling to room temperature, an aqueous saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml) were added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml), and dried over anhydrous sodium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=100:1→25:1) to obtain the entitled compound (148 mg, 91.2%) as a pale yellow solid.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[C-]#N.[Na+].[CH3:32][N:33](C=O)C>CCOCC>[F:9][C:8]([F:11])([F:10])[CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)[CH2:6][C:32]#[N:33]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Product: N#CCC(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
In a 20 mL round-bottomed flask, 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propyl methanesulfonate (850 mg, 1.95 mmol) and sodium cyanide (957 mg, 19.5 mmol) were combined with DMF (30 ml) to give a light yellow solution. The reaction mixture was heated at 60° C. and stirred for 2 h. The reaction mixture was diluted with ether (60 ml), washed with brine and H2O, dried over MgSO4, filtered and concentrated to give crude product as an oil. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 60% ethyl acetate in hexanes) to afford 400 mg (56%) of 4,4,4-trifluoro-3-[2-(3-trifluoromethylphenyl)-morpholin-4-ylmethyl]-butyronitrile as a colorless oil. MH+=367.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[Br:17])(=O)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[Br:17]
Reactant: CC(=O)Nc1ccc(CCCC(=O)O)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc(CCCC(=O)O)cc1Br

Procedure:
A mixture of 0.13 g (0.008662 mol) of 4-acetylamino-3-bromobenzenebutanoic acid and 10 ml of conc. hydrochloric acid was refluxed for 24 hours. The colourless, needle-shaped crystals of Rf 0.53 (eluant: dichloromethane/methanol 9/1 v/v) precipitated after cooling were identified by spectroscopy as the hydrochloride of the desired 4-amino-3-bromobenzenebutanoic acid. The crystals were dissolved in a little water, and the solution formed was adjusted to pH 6 using concentrated potassium carbonate solution. The precipitate was suction filtered, washed with water and dried in a circulating air dryer at 60° C. Yield: 1.35 g (60% of theoretical).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[NH:1]([C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-(2-(3-methoxyphenyl)ethyl)benzoate 0.13 g were added iodobenzene 0.11 mL, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg, and it was stirred at 110° C. for 6 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 18 hours 30 minutes. Iodobenzene 0.11 mL, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 22 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-anilino-4-(2-(3-methoxyphenyl)ethyl)benzoate.
Reaction SMILES: Br.C[O:3][C:4]1[C:5]2[CH:18]=[C:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:6]=2[CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1>O>[O:3]=[C:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([OH:22])=[O:21])=[CH:18][C:5]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(OC)=Cc1ccccc1C2
Agent: Br
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Six milliliters of 47% hydrobromic acid was added to 0.32 g of methyl 11-methoxy-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 11, and the mixture was stirred at 100° to 125° C. for 30 minutes. After the reaction, the reaction mixture was cooled, and water was added. The mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ether was distilled off. Recrystallization of the residue from a mixture of methanol and n-hexane afforded 0.22 g of 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid as colorless needle-like crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:30][C:29]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=1)#[N:9]
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Nc2ccc(F)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (150 mg, 0.380 mmol), 4-fluoroaniline (75 uL, 0.792 mmol), BINAP (40 mg, 0.064 mmol), Pd(OAc)2 (25 mg, 0.11 mmol) and K2CO3 (150 mg, 1.08 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 100 C for 16 h. EtOAc and water were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1S,2R)-2-(4-cyano-3-(4-fluorophenylamino)phenylamino)cyclohexylcarbamate as a crude residue.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1)#[N:14].C([Li])CCC>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]([C:20]1[S:21][C:17]2[CH:16]=[C:15]([C:13]#[N:14])[CH:23]=[CH:22][C:18]=2[N:19]=1)([OH:4])[CH2:2][Cl:1]
Reactant: N#Cc1ccc2ncsc2c1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Li]CCCC
Product: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1

Procedure:
2-Chloro-2',4'-difluoroacetophenone is added to 6-cyanobenzothiazole in the presence of n-butyllithium to form 1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloroethanol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:14]([C:15](OCC)=[O:16])=[C:13]([CH2:20][CH3:21])[CH:12]=[CH:11][N:10]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH2:20][CH3:21])[CH:12]=[CH:11][N:10]=1)[CH3:8]
Reactant: CCOC(=O)c1c(CC)ccnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccnc(CC)c1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (410 mg, 10.8 mmol) was stirred in anhydrous THF (45 mL). A solution of ethyl 2,4-diethylpyridine-3-carboxylate (1.50 g, 7.2 mmol) in anhydrous THF (10 mL) was added at 0° C., and then stirred at room temperature for 2 hours. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (2,4-diethylpyridin-3-yl)methanol was obtained as an oil (1.17 g, 98% yield) and used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C)C=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1>O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Potassium carbonate (10.8 g, 78.1 mmol) and N-(3-bromopropyl)phthalimide (12.1 g, 45.1 mmol) were added to a N,N-dimethylformamide (DMF) solution (80 ml) of 4-fluoro-2-nitrophenol (6.0 g, 38.2 mmol), and the mixture was stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, water (200 ml) was added, and the reaction mixture was then cooled with ice. The precipitated insoluble matter was collected by filtration. After being washed with water (50 ml×3), the substance remaining in the filter was air-dried, giving 13.2 g of powdery pale yellow 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione (yield: 100%).
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16]CC)=[O:15])(=[O:5])[CH3:4]>C(O)C>[C:3]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([OH:16])=[O:15])(=[O:5])[CH3:4]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(C2CCCN2C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCCC1c1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 ml of aqueous 4 N sodium hydroxide solution was added to an ethanol (200 ml) solution of 18.7 g of ethyl 3-(1-acetyl-pyrrolidin-2-yl)-4-benzyloxybenzoate, and the reaction liquid was stirred overnight at room temperature. 15 ml of aqueous 4 N sodium hydroxide solution was added to the reaction liquid, and the reaction liquid was stirred for 7 hours. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was diluted with water, and washed with ether. The aqueous layer was acidified with 6 N hydrochloric acid added thereto, then extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17]([C:19]1[O:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=1)=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:21]3[O:20][C:19]([C:17]([OH:18])=[O:16])=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Product: O=C(O)c1ccc(COc2ccc(-c3ccc(Br)cc3)cc2)o1

Procedure:
5-(4′-Bromo-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 86 mg. Mass spectrum (ES) MH+=373.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)o1
Temperature: 40 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2,6-diamine (4.5 mg, 0.034 mmol) described in Manufacturing Example 13-1-3 and triethylamine (9.4 μL, 0.068 mmol), which was stirred for 3 hours at 40° C. Water was added thereto at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:2) to obtain the title compound (9.2 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: CC(O)c1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCCc1ncc(Br)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3N)[nH]c2=O)cn1
Yield: 57.3 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-aminopyridine (0.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.59 g) were refluxed in pyridine (2 ml) under nitrogen for 9 hours. The pyridine was removed in vacuo and the residual pyridine removed by azeotroping with n-propanol. After chromatography on silica in ethylacetate/ethanol/0.880 ammonia (15:10:2), the residue was crystallised from ethanol-ether and water (2 drops) to give 2-[4-(5-bromo-3-aminopyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl) 4-pyrimidone (0.52 g), m.p. 196°-197° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:14]=1>CN(C=O)C>[Br:8][C:9]1[C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:11][CH:12]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:14]=1
Reactant: OCC1CC1
Reactant: CS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A solution of cyclopropylmethanol (146 uL, 1.8 mmol) stirred in DMF (3 mL) at 0° C. was treated with NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring at 0° C. for 30 min, the reaction mixture was treated with a solution of 3-bromo-2-chloro-5-methylsulfonylpyridine (400 mg, 1.5 mmol) in DMF (3 mL) by dropwise addition. After the ice bath was removed, the mixture was stirred at rt for 14 h. The reaction mixture was treated with water and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 85%) in hexanes to give the title compound (298 mg, 65%). LCMS (M+H)+=307.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1>>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Fc1cc(F)cc(Br)c1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: [(S)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester and 1-bromo-3,5-difluorobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid (4 g) is dissolved in 20 mL of methanol. To the solution, 3 mL of concentrated sulfuric acid is added. The reaction mixture is brought to gentle reflux over 24 hours. Methanol is removed and the residue is diluted with water. The compound of interest is extracted into ethyl acetate. The organic layer is extracted with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. Solvent is removed and the product is in the form of off-white powders.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccc2ncccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2ncccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
To a solution of 5-aminoquinoline (1.0 g, 6.9 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (40 mL) was added trichloroacetyl chloride (1.4 g, 7.7 mmol) at 0° C., and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated, and to the residue was added ethyl acetate, and the resulting mixture was extracted three times with 1 N hydrochloric acid. The aqueous layers were combined and neutralized with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (1.9 g, yield 94%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:13]=[O:20])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
One equivalent of 3,4-dinitrotoluene and 2 equivalents of N-bromosuccinimide in carbon tetrachloride is irradiated with a 500 W tungsten lamp for 4 hours. The mixture is filtered and the filtrated is shaken with a solution of aqueous potassium carbonate. The organic layer is evaporated in vacuo to give 3,4-dinitrobenzaldehyde.