Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[C:19]([S:23][S:24][N:25]([C:27](F)=[O:28])[CH3:26])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.FC(NC)=O>C1(C)C=CC=CC=1>[C:19]([S:23][S:24][N:25]([CH3:26])[C:27](=[O:28])[O:13][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[OH:1])=[C:11]([CH3:12])[CH:10]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(SSC(C)(C)C)C(=O)F
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Agent: CNC(=O)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)SSC(C)(C)C)cc(C)c1N=Cc1ccccc1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a manner identical to that described in Example II, Part A, 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol was prepared. To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 4.83 grams (0.020 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol, 3.95 grams (0.020 moles) of N-(tertbutylthiosulfenyl)-N-fluorocarbonyl-N-methylamine, 2.12 grams (0.021 moles) of triethylamine and 200 milliliters of toluene. The resulting reaction mixture was heated to a temperature of 50° C. in an oil batch for 16 hours with continuous stirring. After this heating and stirring period, 1.0 grams (0.0041 moles) of N-tert-butylthiosulfenyl)-N-fluorocarbonyl-N-methylamine and 0.5 grams (0.005 moles) of triethylamine were added to the reaction mixture and heating continued for an additional 3 hours at a temperature of 50° C. with continuous stirring. The reaction mixture was cooled to room temperature and then washed twice with water, twice with a 2% aqueous sodium bicarbonate solution and once with a saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give a red oil. Purification of the red oil by column chromatography yielded 2.02 grams (0.0048 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenyl N-(tert-butylthiosulfenyl)-N-methylcarbamate in the form of a yellow solid having a melting point of 121°-124° C. and the following structural formula: ##STR24##
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(C)=O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2,5-dihydroxybenzoate (1.5 g, 8.92 mmol), potassium carbonate (7.50 g, 54.2 mmol), and dry acetone (100 ml) was stirred at room temperature for 30 min. To the mixture was added TsCl (1.72 g, 9.00 mmol) portionwise and the mixture was refluxed for 7 h. The reaction mixture was used in the next step directly.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[C:5]=1[CH3:15].Cl.Cl[CH2:19][C:20]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][N:21]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CC(O)C>[F:16][CH:2]([F:1])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][N:21]=3)=[N:10][C:6]=2[C:5]=1[CH3:15]
Reactant: COc1ccnc(CCl)c1C
Reactant: Cc1cc2[nH]c(S)nc2c(C)c1OC(F)F
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: COc1ccnc(CSc2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1C

Procedure:
2.0 g of 5-difluoromethoxy-4,6-dimethyl-1H-benzimidazole-2-thiol and 1.72 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride are heated in 30 ml of 2-propanol for 4 h to the boil. This gives 3.6 g of the dihydrochloride of the title compound. This is dissolved in water and concentrated hydrochloric acid, the solution is clarified with activated charcoal, the product is precipitated with dilute sodium hydroxide solution and the precipitate is recrystallised from butanol. This gives 2.6 g (85%) of the title compound (m.p. 190°-191° C.).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[C:14]=2[F:22])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[F:22])[O:11][CH3:12])=[CH:24][CH:25]=1)#[N:2]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1Oc1ccccc1
Reaction time: 24 h
Yield: 58.4 %

Procedure:
A mixture of (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (150 mg), phenyl boronic acid (58 mg), copper (II) acetate (79 mg), pyridine (0.18 ml) and activated molecular sieves (4 A) at rt in CH2Cl2 under an argon atmosphere was stirred for 24 h. More copper (II) acetate (40 mg), phenyl boronic acid (29 mg) and pyridine (0.9 ml) were added to the mixture and stirring was continued for 16 h. The mixture was filtered and the cake washed with 15 ml CH2Cl2. The filtrate was washed with 1.0 N HCl (25 ml), 1.0 N NaOH (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a brown gum. The crude product was purified by flash chromatography (cyclohexane=5 cyclohexane/EtOAc 2:3) to give (RS)-N-(4-Cyano-benzyl)-2-(2-fluoro-4-methoxy-3-phenoxy-phenyl)-2-methoxy-acetamide (107 mg) as an off-white foam. MS 421.2 ([M+H]+)
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH2:2][CH2:3][CH3:4].O1CCCC1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16].C(OCC)(=O)C>O>[CH2:1]([N:5]1[C:15](=[O:16])[C:14](=[O:18])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN1C(=O)NC(=O)C1=O
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
3.6 g of butylurea was added to 100 ml of anhydrous tetrahydrofuran and the suspension was stirred in an ice-water bath. 4.3 g of oxalyl chloride was added dropwise to the suspension, and the stirring was continued for 30 minutes in an ice-water bath. 100 ml of ethyl acetate and 30 ml of water were added to the reaction mixture and the organic layer was obtained by extraction, The water layer was further extracted with 60 ml of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated to dryness, the crude residue was recrystallized from ethyl acetate-hexane to give 5.1 g of 1-butylimidazolidinetrione in the form of colorless needle crystals. The resulting compound was suspended to 400 ml of 0.1N ammonium aqueous solution and stirred for 8 hours at room temperature. Further, 5 ml of 28% ammonium aqueous solution was added to the solution and stirred for 14 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in methanol. 3 ml of conc. hydrochloric acid was added thereto. The solution was concentrated under reduced pressure, and the solid precipitate was filtered off, washed with water sufficiently, and recrystallized from water-methanol to give 1.8 g of 5-butyloxaluric acid (compound 3) in the form of colorless needle crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][Cl:22])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[C:29]([Cl:30])=[CH:28][N:27]=[C:26]2[O:31][CH2:32][O:33][C:25]=12>>[Cl:22][CH2:21][CH2:20][O:19][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][C:24]3[C:29]([Cl:30])=[CH:28][N:27]=[C:26]4[O:31][CH2:32][O:33][C:25]=34)=[N:3][CH:4]=[N:5]2)=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=1
Reactant: ClCCOc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: ClCCOc1cc(OC2CCOCC2)c2c(Nc3c(Cl)cnc4c3OCO4)ncnc2c1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 37% yield; NMR Spectrum: (CDCl3) 2.0 (m, 2H), 2.3 (m, 2H), 3.65 (m, 2H), 3.9 (m, 2H), 4.1 (m, 2H), 4.4 (m, 2H), 4.8 (m, 1H), 6.2 (s, 2H), 6.65 (s, 1H), 6.9 (s, 1H), 7.8 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); Mass Spectrum: M+H+ 479 and 481.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@H:15]3[S:14](=[O:42])[CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS(=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To an ice cold solution of 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3.0 g; 6.16 mMol.) in dichloro-methane (50 ml) is added m-chloroperbenzoic acid (1.32 g: 1 Eq.), and the mixture is stirred for 1 hour under ice cooling. The reaction mixture is diluted with aqueous 5% sodium thiosulfate and extracted with dichloromethane. The extract is washed with aqueous sodium hydrogen carbonate, dried, and concentrated in vacuum to give 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide (1.66 g). Yield: 53.5%.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[CH2:30][CH2:31][CH3:32])=[CH:8][CH:7]=1>CO>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[C:14]([CH2:30][CH2:31][CH3:32])[N:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]([OH:33])=[O:4])=[CH:11][CH:10]=3)[C:17]=2[CH:18]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1nc2ccc(C(=O)c3ccccc3)cc2n1Cc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2ccc(C(=O)c3ccccc3)cc2n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of potassium hydroxide (1.0 g in 10 mL of water) was added to a solution of 4-(6-benzoyl-2-propyl-benzoimidazol-1-ylmethyl)-benzoic acid methyl ester (1.0 g) in methanol (25 mL). The mixture was heated at reflux for a period of 3 hours. The reaction mixture was cooled to ambient temperature. The methanol was evaporated under vacuum. The residue was diluted with water (30 mL), then extracted with ethyl acetate (24 mL). The aqueous phase was acidified with 1N HCl. The precipitated solid was collected and air dried to afford the tide compound (0.6 g, 63% yield) as a white solid m.p. 295-296° C. Anal. Calcd. for C25H22N2O3: C, 75.36; H, 5.57; N, 7.03. Found: C, 75.03; H, 5.65; N, 6.86. Mass spectrum (PBEI; M+) mlz 398. 1H-NMR (DMSO-d6; 400 MHz): δ13.0 (br s, 1H), 7.91 (d, 2H), 7.82 (s, 1H), 7.72 (d, 1H), 7.58-7.64 (m, 4H), 7.47 (t, 2H), 7.18 (d, 2H), 5.67 (s, 2H), 2.88 (t, 2H), 1.78 (m, 2H), and 0.94 ppm (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(F)cc1O
Temperature: 60 °C
Yield: 126.2 %

Procedure:
To 4-chloro-3-fluorophenol (20 g, 100 mmol, from Aldrich) was added acetyl chloride (14.1 mL, 199 mmol) under N2 with stirring. The resulting mixture turned into a clear solution at room temperature and was heated at 60° C. for 2 hours. To the resultant mixture was added aluminum trichloride (25.0 g, 187 mmol) in portions and the mixture was heated at 180° C. for 30 minutes. The solids slowly dissolved at high temp. The reaction mixture was then cooled to room temperature while the flask was swirled carefully in order for the solid to form a thin layer inside the flask and then slowly quenched with 1.0 N HCl (300 mL) while cooling in an ice-bath and stirred overnight. The yellow precipitate was washed well with water and dried under vacuum to give the desired product as a yellow solid (23.8 g), which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:24][N:23]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3ccnc(C)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=303.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([N-]C(C)C)(C)C.[Li+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH2:16]([CH:4]([CH2:3][CH2:2][CH3:1])[C:5]([OH:7])=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(=O)O
Reactant: ClCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Cc1ccccc1)C(=O)O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
N-Valeric acid (1 g) was dissolved in 75 ml of tetrahydrofuran and treated with 2 equivalents of lithium diisopropylamide at room temperature. The solution was then heated to 40° C. for 30 minutes followed by the addition of 1.1 ml of benzyl chloride. After 1.5 hours at 40° C., the reaction mixture was cooled to room temperature, poured into 300 ml of water and extracted with diethyl ether (2×200 ml). The aqueous solution was then acidified with 1M hydrochloric acid and extracted with diethyl ether (2×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified 10 by radial chromatography (40-50% ethyl acetate in hexane, 2 mm plate) to yield 1.63 g of 2-benzylpentanoic acid (87% yield).
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([NH:25][C:26](=[O:35])[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[C:14]2=[O:24])=[CH:9][CH:8]=1)C.Cl>>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]=1[C:26]([NH:25][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH3:23])[C:14]2=[O:24])=[CH:9][CH:8]=1)[C:4]([OH:36])=[O:3])=[O:35]
Reactant: CCOC(=O)[C@H](Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: Cl
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The mixture of (2S)-2-(2-chloro-6-methyl-benzoylamino)-3-[4-(4-methyl-1,3-dioxo-1,3-dihydroisoindole-2-yl)phenyl] propionic acid ethylester and 3N hydrochloric acid was stirred at 80° C. overnight. The solvent was removed and the residue was purified by reverse phase HPLC to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)methanesulfonamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and methane sulfonyl chloride to give a tan solid (57% yield). 1H-NMR (CDCl3): δ 8.71 (s, 1H), 7.60 (m, 1H), 7.26 (m, 1H), 7.20 (d, 1H), 4.71A4.59 (m, 2H), 3.07 (s, 3H), 2.67 (m, 2H), 2.22 (m, 1H), 2.00-1.78 (m, 3H); MS m/z 343 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:26][CH2:27]2)[CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(CC=O)cc1F
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(F)cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1F

Procedure:
A solution of 2,6-difluoro-4-(2-oxoethyl)benzonitrile (185 mg, 1.0 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (200 mg, 0.85 mmol) and NaBH(OAc)3 (720 mg, 3.4 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 20 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.15˜8.17 (d, J=8.6 Hz, 2H), 7.37˜7.39 (d, J=8.6 Hz, 2H), 6.92˜6.94 (d, J=8.6 Hz, 2H), 2.50˜3.11 (m, 16H). MS m/z: 401 (M+1)+. (0.16 μM)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=4)[CH2:13][C:12]3([CH3:26])[CH3:25])=[C:8]([C:27]([NH2:29])=[O:28])[CH:7]=[N:6][N:5]2[CH:30]=1.[F:31][C:32]([F:37])([F:36])[C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[C:23]([C:20]1[N:19]=[N:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:30]=[C:2]([NH:35][C:33](=[O:34])[C:32]([F:37])([F:36])[F:31])[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:27]([NH2:29])=[O:28])[C:12]([CH3:25])([CH3:26])[CH2:13]2)=[CH:22][CH:21]=1)#[N:24]
Reactant: CC1(C)CN(c2ccc(C#N)nn2)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: NC(=O)C(F)(F)F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CN(c2ccc(C#N)nn2)CCC1Nc1c(C(N)=O)cnn2cc(NC(=O)C(F)(F)F)cc12
Temperature: 92.5 °C
Reaction time: 16 h

Procedure:
A mixture of 6-bromo-4-(1-(6-cyanopyridazin-3-yl)-3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 4 of Example 1 (20 mg, 0.043 mmol), 2,2,2-trifluoroacetamide (9.6 mg, 0.085 mmol), copper(I) iodide (1.6 mg, 8.52 μmol), potassium carbonate (11.8 mg, 0.085 mmol) and N1,N2-dimethylethane-1,2-diamine (10 μl, 0.094 mmol) in dioxane (0.5 mL) was pumped and backfilled with nitrogen twice. The reaction vial was sealed and stirred at 90-95° C. for 16 h. LCMS analysis showed the reaction was ˜40% complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-55% B over 25 minutes, then a 15-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound, assumed as TFA salt (4 mg, 15% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (1 H, s), 7.96 (1 H, d, J=1.66 Hz), 7.55-7.58 (1 H, m), 7.15-7.21 (2 H, m), 4.22 (1 H, d, J=13.04 Hz), 4.17 (1 H, dd, J=10.40, 3.75 Hz), 3.42-3.51 (1 H, m), 3.20 (1 H, d, J=13.87 Hz), 2.24 (1 H, dd, J=13.87, 3.61 Hz), 1.85-1.94 (1 H, m), 1.11 (3 H, s), 1.10 (3 H, s); MS (ES+) m/z: 502.13 (M+H); LC retention time: 2.225 min (analytical HPLC Method C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C(=[NH:51])(C1C=CC=CC=1)C1C=CC=CC=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([NH2:51])[CH:3]=3)[N:7]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(N)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 2.0 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole obtained in Production Example II-9-c in 20 ml toluene at room temperature were added 0.73 g of benzophenoneimine, 95 mg of tris(dibenzylideneacetone)(chloroform)dipalladium(0), 0.17 g of 2,2′-bis(diphenylphosphino)-.1,1′-binaphthyl and 0.53 g of sodium tert-butyrate, and the mixture was heated under reflux for one day. The mixture was diluted with water and ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 30 ml of tetrahydrofuran, 10 ml of 5 N hydrochloric acid was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), and the resulting obtained crystals were washed with diethyl ether, to give 0.86 g of the title compound as colorless crystals.