Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 409.09 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (3.25 g, 26.4 mmol) in tetrahydrofuran (20 mL)/1N aqueous sodium hydrogen carbonate solution (39 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 3 hr. The aqueous layer was separated, and extracted with ethyl acetate (100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate (45 mL)/hexane (45 mL) to give the title compound (5.95 g, 77%) as a colorless powder.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Cl[CH2:23][C:24]#[N:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:24]#[N:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: N#CCCl
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.05 h
Yield: 87.4 %

Procedure:
In an atmosphere of argon, a mixture of 26 mg (3.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 3 minutes. The mixture was further stirred for 1 hour. To the mixture was then added a mixture of 313 mg of chloroacetonitrile and 1 ml of DMF. The mixture was then stirred for 3 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 805 mg of [2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetonitrile was obtained as a low polarity substance, and 70 mg of 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetonitrile was obtained as a high polarity substance.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[CH:26][C:27]([F:34])=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:34][C:27]1[CH:26]=[CH:25][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: ClCCl
Product: COC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F

Procedure:
tert-Butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate was synthesized as described for INTERMEDIATE 32 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Eastwood, P. R. Tetrahedron Lett., 41, 19, 2000, 3705-3708) and methyl 5-bromo-2-fluorobenzoate as starting material and PdCl2dppf.CH2Cl2 as a catalyst.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(OC2CCCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclopentanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, sodium hydride (20 mg) was added and the mixture was stirred an additional 1 h at 90° C. The reaction was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 222 mg of 159.1 as a colorless oil. LCMS (2 min gradient) RT=2.01 min, 242.15 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([CH3:11])=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:10][C:9]1[C:4]([C:1](=[N:13][OH:14])[CH3:2])=[N:5][CH:6]=[C:7]([CH3:11])[N:8]=1
Reactant: CC(=O)c1ncc(C)nc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ncc(C)nc1C
Yield: 87.1 %

Procedure:
2-Acetyl-3,5-dimethylpyrazine (2.65 g), hydroxylamine hydrochloride (2.5 g) and sodium acetate trihydrate (3.5 g) were refluxed in methanol (50 ml) for 1 hour. The reaction mixture was concentrated, diluted with water (75 ml) and extracted with ethyl acetate. The combined extracts were dried and concentrated to give an oil which was triturated with ether and 60°-80° C. petrol to give 3,5-dimethyl-2-(1-hydroximinoethyl)pyrazine (2.54 g, 87% yield) as a white solid (m.p. 85°-89° C.) and as a 1:1 mixture of (E/Z) isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1CCC1CCCN21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCC1CCCN21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl 7-amino-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 33, 0.575 g) in pyridine (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give a pale yellow solid which was triturated with a mixture of ether and cyclohexane (1:1) to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (0.966 g)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 50 ml of chloroform was added 7-methylcoumarin (10 g, 62.4 mmol) and N-bromosuccinimide (11.1 g, 62.4 mmol). The suspension was then refluxed for 24 hours at which time a clear solution resulted. Reflux was continued for five days. At this point a spherical lump of crystals had formed. The reaction mixture was cooled to room temperature and was then placed in the refrigerator at 0° C. for 24 hrs. The crystals were collected by filtration and washed with a small amount of cold chloroform. After brief evacuation to remove chloroform, the crystals were dissolved in a minimum amount of boiling acetone and allowed to crystallize for several days. The crystals were collected by filtration and washed with a little cold acetone. After drying in vacuo the yield was , 7.15 g (48% of theory). The melting point was 179.5°-181.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][CH2:11][OH:15])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCO)nc1
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-5-nitro pyridine (2.03 g, 10 mmol), 3-butyn-1-ol (1.05 g, 15 mmol), copper(I) iodide (19 mg, 0.1 mmol), dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.02 mmol), triethylamine (5.06 g, 50 mmol) in acetonitrile (30 mL) was stirred for 4 h. The reaction mixture was evaporated to dryness and loaded onto a Biotage KPSil60A cartridge, and purified by flash chromatography using Et2O-DCM (1:9) as eluent to afford 4-(5-nitropyridin-2-yl)but-3-yn-1-ol as an oil (1.42 g, MS m/e MH+ 193). This oil (1 g, 5.21 mmol) was stirred in methanol (50 mL) and 10% palladium on carbon (0.2 g) was added and the reaction stirred under an atmosphere of hydrogen. The reaction was filtered through Celite® and concentrated in vacuo to afford the title compound as an oil (0.87 g). 1H NMR δ 7.99 (1H, s), 6.93 (2H, s), 3.86 (2H, t), 3.55 (2H, s), 2.73 (2H, t), 1.70-1.74 (2H, m), 1.60-1.62 (2H, m); MS m/e MH+ 167.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][C:22](O)=[O:23]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][C:22]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:23]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)COc1nc2ccccc2s1
Product: O=C(COc1nc2ccccc2s1)N1CCCc2ccccc21
Yield: 28 %

Procedure:
Compound 62 was synthesized according to General Procedure B using compound 3 and compound 61 to yield 62 (183 mg, 28%): MS (APCI): m/z 325 [M+H]+. Anal. Calcd. for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.64. Found: C, 66.88; H, 4.94; N, 8.60.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20](OC3C=CC=CC=3)[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20]([NH2:5])[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCOCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc(C)cc2n1CCOCc1ccccc1
Yield: 51.4 %

Procedure:
Ammonium acetate (25 g, 0.32 mol) and 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.5 g, 6.0 mmol) were heated at 150° C. in a sealed tube for 22 hours. The resulting solution was adjusted to pH 14 with the addition of 20% sodium hydroxide, and water (50 mL) was added. The mixture was stirred for several hours to provide a yellow precipitate, which was isolated by filtration. The precipitate (1.75 g) was recrystallized from a 50:50 mixture of hexane:ethyl acetate (29 mL/g), and the crystals were isolated by filtration and dried under vacuum for 23 hours at 60° C. to provide 1.05 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine as small white crystals, mp. 127–128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccccn2)cc1Cl

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (180 mg, 0.42 mmol) was dissolved in 20 ml of dichloromethane, m-CPBA (80 mg, 0.46 mmol) was added and reacted at room temperature for 12 h, washed with water after reaction, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid, and this product was directly used in the next reaction without purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[CH2:8])[C:5]([OH:7])=[O:6].[CH2:10]([O:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][NH:18][CH2:8][CH:4]([CH2:3][CH:2]([CH3:9])[CH3:1])[C:5]([OH:7])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(CC(C)C)C(=O)O
Reactant: NOCc1ccccc1
Product: CC(C)CC(CNOCc1ccccc1)C(=O)O

Procedure:
A solution of 4-methyl-2-methylenepentanoic acid (3.5 g) and O-benzylhydroxylamine were heated at 120° for 8 h. The reaction mixture was then partitioned between 50 mL of 1.0N NaOH and 50 mL of diethyl ether. The aqueous portion was separated, acidified to pH 3 with 10% HCl and washed with 50 mL of ether. Ion exchange chromatography (Dowex-50W) eluting with 20% pyridine/water gave 2-(benzyloxyaminomethyl)-4-methylpentanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Nc2cccnn2)cc1
Reactant: BrCc1ccc(Br)cc1
Product: N#Cc1ccc(N(Cc2ccc(Br)cc2)c2cccnn2)cc1

Procedure:
3-[(4-Cyanophenyl)amino]pyridazine and 4-bromobenzyl bromide
Reaction SMILES: [F:1][CH:2]([F:9])[N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1>>[Br:17][C:15]1[CH:16]=[C:11]([NH:8][C:6]2[CH:5]=[N:4][N:3]([CH:2]([F:9])[F:1])[N:7]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Nc1cnn(C(F)F)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2cnn(C(F)F)n2)c1=O
Yield: 70 %

Procedure:
Following the procedure of Example 151f, and starting with 159b (170 mg, 1.25 mmol, 1.0 eq.) and 3,5-dibromo-1-methylpyridin-2(1H)-one (504 g, 1.89 mmol, 1.5 eq.) afforded 159c as a light yellow solid (280 mg, 70%). MS-ESI:[M+H]+ 320.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (242 mg, 1 mmol), 2-methylpropan-2-amine (110 mg, 1.5 mmol), EDCI (382 mg, 2 mmol) and DMAP (244 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature for 3 hours. Then the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude residue was used to the next step without further purification. MS: (M+H)+=297.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>[Pd].CCO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C2CC(O)(c3ccc(OC)cc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CC(c3ccc(OC)cc3)C2)cc1

Procedure:
1.3-bis(p-methoxyphenyl)cyclobutanol (13.2 g., 0.046 mole), 3.0 g. of 10% Pd/c, 1 ml. of 70% HClO4, and 100 ml. of 95% EtOH is shaken under 50 psi of H2 until hydrogen absorption is complete. The catalyst is removed by filtration and the filtrate is evaporated. A solution of the residue in ether is washed (5% Na HCO3, water) and dried (MgSO4). Evaporation of the ether yields a residue (11.4 g.) which is recrystallized (EtOH), affording 6.8 g. (55%) of the desired intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH4+].[OH-].[CH3:20][N:21](C)C=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:20]#[N:21])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C#N)c(OC)ccc12
Temperature: 180 °C

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H) 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR (DMSO-d 6) δ 4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:11][NH2:12])[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].ClC1C=C(N2[C:25]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)=[CH:24][C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=N2)C=CC=1F>>[Cl:33][C:28]1[CH:27]=[C:26]([C:25]2[N:11]([C:6]3[CH:7]=[CH:8][C:9]([F:10])=[C:4]([C:2]#[N:3])[CH:5]=3)[N:12]=[C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:24]=2)[CH:31]=[C:30]([F:32])[CH:29]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: N#Cc1cc(NN)ccc1F
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 1A and 3-cyano-4-fluorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.66 g of the title compound with 49% purity (100% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](N(OC)C)=[O:9])[S:4][N:3]=1.I[Mg][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.Cl>O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[O:9])[S:4][N:3]=1
Reactant: I[Mg]c1ccsc1
Reactant: CON(C)C(=O)c1snc(Cl)c1Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccsc1)c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of 3,4-dichloro-N-methoxy-N-methyl-1,2-thiazole-5-carboxamide (3.80 g, 15.7 mmol) in tetrahydrofuran (130 mL) at −5° C. was added dropwise a solution of iodo(3-thienyl)magnesium in tetrahydrofuran (0.3 M, 158 mL, 47.4 mmol). After stirring at room temperature for 72 h, the reaction was worked-up by the addition of aq. HCl (1 M) until pH<7. After removal of the tetrahydrofuran in vacuo, the aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford (3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methanone [3.00 g, yield 65%; HPLC/MS: m/z=264 (M+H); log P(HCOOH)=3.31].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([CH3:25])[CH3:24]>>[CH:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 152 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-bromopropane and conditions outlined in procedure V. M.p.=197-198° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92-7.88 (m, 1H), 7.82-7.74 (m, 2H), 7.6-7.52 (m, 1H), 3.06 (s, 2H), 2.8-2.63 (m, 3H), 2.6-2.48 (m, 2H), 2.1-1.94 (m, 2H), 1.85-1.7 (m, 2H), 1.01 (d, J=3.1 Hz, 6H); LCMS: 344 [M+H].