Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[S:7][C:8]=1[CH3:9])([O-:3])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:9]/[C:8]1[S:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of methyl 4-nitro-5-methylthiophene-2-carboxylate (23 g, 114 mmol) in N,N-dimethylformamide dimethyl acetal (115 ml) was stirred at 110° C. for 1 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to about half amount, and poured into water (500 ml). The precipitated solid was collected by filtration, washed with water (500 ml×2), and dried under reduced pressure to give methyl (E)-5-(2-dimethylaminovinyl)-4-nitrothiophene-2-carboxylate (28 g, yield 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:17][C:18](=[O:27])[C:19]1[C:24](Cl)=[CH:23][CH:22]=[CH:21][C:20]=1Cl.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(=O)([O-])[O-].[K+].[K+]>[Cu-]=O.CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:23][CH:22]=[CH:21][C:20]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(Br)cnc12)c1c(Cl)cccc1Cl
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc2c(-n3ccnc3)c(Br)cnc12)c1c(-n2ccnc2)cccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (50 mg) and N-methylpyrrolidone were added imidazole (11 mg), potassium carbonate (22.4 mg) and copper(I) oxide (7.74 mg), and the mixture was stirred for 1.5 hours at 60° C. and for 1 hour at 80° C. The mixture was partitioned between dichloromethane and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and crystallized from diisopropyl ether to give 3-bromo-8-[2,6-bis(imidazol-1-yl)benzoylamino]-4-(imidazol-1-yl)quinoline (17 mg).
Reaction SMILES: C([Mg:4][Br:5])(C)C.Cl[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].BrC1C(F)=C(F)C(F)=C(F)C=1F>C(OCC)C>[C:7]1([Mg:4][Br:5])[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Agent: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Reaction time: 7.5 h

Procedure:
To a diethyl ether solution of isopropyl magnesium bromide, chloropentafluorobenzene is added at 0° C. to 40° C. under nitrogen with stirring in a period of thirty minutes, such that the isopropyl magnesium bromide is in 1.03 to 1.05 molar excess of the chloropentafluorobenzene. The mixture is stirred at 47° C. to 53° C.; after 5 to 10 hours, bromopentafluorobenzene is added to react with the excess isopropyl magnesium bromide, and the mixture is stirred at 25° C. for 1 hour. Any excess bromopentafluorobenzene is back-titrated in situ with isopropyl magnesium bromide to form more C6F5MgBr. The yield of C6F5MgBr is 96.1%, and 3.9% C6F5C1 remained, as determined by 19F NMR, using C6H5CF3 as a reference; no trace of iPrMgBr was seen with 1H NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:30][CH2:29][O:28][CH3:27])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COCCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and 2-chloroethyl methyl ether (83 μL, 0.91 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 1:1:2 followed by trituration with diethyl ether afforded 24 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.45 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[Br:21]Br>CC(O)=O.O>[Br:21][C:6](=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C=NNc1ccc(Cl)nn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(Br)=NNc1ccc(Cl)nn1
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of compound 1-ethoxycarbonylmethylene-2-(6-chloro-3-pyridazinyl) hydrazine (11.4 g, 0.05 mol) and sodium acetate (11 g, 0.05 mol) in 50 mL of HOAc, bromine (8 g, 0.05 mol) in HOAc was added dropwise during 20 min. Stirring was continued for 3 h, the mixture was diluted with water (1 L), the precipitated crystals were filtered off, washed with water to give product ethyl 2-bromo-2-(2-(6-chloropyridazin-3-yl)hydrazono)acetate as a yellow solid (10 g, 66%). 1H NMR (300 MHz, d6-DMSO): δ 9.33 (br, 1H), 7.69-7.66 (d, J=9.0 Hz, 1H), 7.50-7.47 (d, J=9.0 Hz, 1H), 4.44-4.37 (q, 2H), 1.43-1.39 (t, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][C:12]1[C:14]2[C:15](=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])[C:21](=[O:23])[NH:2][N:3]=1
Reactant: NN
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(Br)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
Hydrazine hydrate (0.110 mL, 1.48 mmol) was added to methyl 4-(2-(3-bromophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (49) (0.470 g, 1.34 mmol) in acetic acid (20 mL). The resulting solution was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a beige solid (0.253 g, 56.7% yield); 1H NMR (400.132 MHz, MeOD) δ 2.18 (3H, s), 2.50 (3H, s), 4.03 (2H, s), 7.04-7.11 (2H, m), 7.25 (2H, m); m/z (LC-MS, ESI+), RT=1.84 min (M+H=333.97).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[Cl:27][C:28](OC(Cl)(Cl)Cl)=[O:29]>ClCCl>[CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:16])([CH3:17])[N:7]([C:28]([Cl:27])=[O:29])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC1=NN(C(=O)Cl)C(C)(C)C1c1ccccc1
Yield: 43 %

Procedure:
To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate (IV-1) (0.47 gram, 1.43 mmol) in dichloromethane (10 ml) was successively added DIPEA (0.35 ml, 2.07 mmol) and trichloromethyl chloroformate (0.25 ml, 2.07 mmol, dissolved in 10 ml dichloromethane) at 0° C. and the resulting solution was allowed to attain room temperature and subsequently reacted at room temperature for 1 hour in a nitrogen atmosphere. Subsequent Sepacore column chromatographic purification (eluant: petroleum ether/diethyl ether=93/7 (v/v)) gave pure 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1-carbonyl chloride (Intermediate VIII-1) (0.20 g, 43% yield). (Intermediate VIII-1). 1H-NMR (400 MHz, CDCl3) δ 0.87 (t, J=7, 3H), 1.11 (s, 3H), 1.27-1.39 (m, 2H), 1.45-1.59 (m, 5H), 2.10-2.20 (m, 1H), 2.36-2.46 (m, 1H), 3.91 (s, 1H), 7.01 (br d, J˜8 Hz, 2H), 7.30-7.40 (m, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1.O[CH2:27][C:28]1([CH2:32][CH2:33][CH3:34])[CH2:31][O:30][CH2:29]1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([O:23][CH2:27][C:28]2([CH2:32][CH2:33][CH3:34])[CH2:31][O:30][CH2:29]2)=[O:22])=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCCC1(CO)COC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCC1(COC(=O)c2ccc(Cl)nc2)COC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of dicyclohexylcarbodiimide (2.0 gm.) in dry dimethylformamide (5 ml.) was added to a stirred solution of 6-chloronicotinic acid and 3 -hydroxymethyl-3-n-propyloxetane in dry dimethylformamide (15 ml.) at room temperature. The reaction mixture was stirred at room temperature for 60 hours. The mixture was filtered and the solid was washed with diethyl ether (50 ml.). The filtrates were washed with water and then with 5% aqueous sodium carbonate solution. The etheral solution was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The residue was purified by chromatography on silica, eluting with 1% triethylamine:chloroform. (3-n-propyl-oxetan-3-yl)methyl 6-chloro-3-pyridinecarboxylate was obtained as an oil, which solidified on standing (289 mg.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1COc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1COc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of methyl 5-chloro-2-[(2-chlorophenoxy)methyl]benzoate (step 1, 103 mg, 0.33 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was 2 N sodium hydroxide (1 mL) and the mixture was stirred at room temperature for 16 hours. After removal of solvent, the residue was diluted with water (5 mL) and the solution was acidified with 2 N hydrochloric acid. Precipitate was collected by filtration, washed with water and dried in vacuo to afford 85 mg (86%) of the title compound:
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][C:10]2[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:6][C:5]=2[C:4](=[O:36])[CH2:3]1.CC(C)C(O)=O.[CH3:44][N:45]([CH3:48])[CH:46]=O>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:8]3[C:7]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:6][C:5]4[C:4](=[O:36])[C:3](=[CH:44][N:45]([CH3:48])[CH3:46])[C:2]([CH3:37])([CH3:1])[CH2:11][C:10]=4[N:9]=3)=[CH:17][CH:16]=2)[CH2:21][CH2:20][CH2:19]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2C1
Reactant: CN(C)C=O
Solvent: CC(C)C(=O)O
Product: CN(C)C=C1C(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2CC1(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Tert-butyl (1-(4-(7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (1 g, 2 mmol) was dissolved in 10 ml of anhydrous N,N-dimethylfomamide dimethylformamide dimethyl acetate. The resulting mixture was heated to 100° C. under a nitrogen atmosphere for 48 hours. TLC and LC-MS analysis showed complete consumption of the starting material. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was slurried in n-hexane (10 ml) for 1 hour. The suspension was filtered and the solid was dried until constant weigh to give the desired product as a bright yellow solid (420 mg, 76% yield). LCMS (Method A): RT=8.51 min, M+H+=552; RT=8.81 min, M+H+=525 (tert-butyl(1-(4-(6-(hydroxymethylene)-7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)cyclobutyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:44]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([CH3:44])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C

Procedure:
Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (0.5 g, 0.8 mmol) were dissolved in 1 ml dimethylformamide 0.1 g sodium carbonate was added under stirring at room temperature. Methyl iodide (70 μl, 0.16 g, 1.1 mmol) was added dropwise under vigorous stirring at room temperature by a syringe. The reaction mixture was stirred at room temperature overnight. Water was added to the stirred suspension, and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate twice (2×20 ml). The organic layer was dried over sodium sulfate. After drying of the organic layer, the solvent was evaporated under reduced pressure at 46° C. The brownish remaining crude product was used for the further synthesis without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:21]O>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH3:21])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1-c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 5-bromo-[1,1′-biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCl2 (10 mL) dropwise. The reaction mixture was heated to 70° C. for 2 h, then cooled to RT. The mixture was concentrated, adjusted to pH=7-8 with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 50:1) to afford methyl 5-bromo-[1,1′-biphenyl]-2-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:5]=2[NH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1n[nH]c2c(-c3ccccc3F)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (150 mg), 2-fluorophenylboronic acid (93 mg), tetrakis(triphenylphosphine)palladium(0) (51 mg), potassium carbonate (122 mg), 1,2-dimethoxyethane (5.0 mL) and water (0.5 mL) was stirred overnight at 90° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (38.3 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:64][C:65](C1C=CC=CC=1S(Cl)(=O)=O)=[O:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O1CCOCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:65]([O:64][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:66])(=[O:40])=[O:39])[CH2:27][O:28][C:29]3[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Reactant: O=C(OCc1ccccc1)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 ml of 4 N hydrogen chloride in dioxane and 2.5 ml of dioxane were added to 500 mg (0.854 mmol) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(4-iodobenzenesulfonylamino)propoxy]benzonitrile. The mixture was stirred at room temperature for 24 hours, and the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 8 ml of DMF, and 0.49 ml (2.56 mmol) of di-isopropylethylamine and 398 mg (1.28 mmol) of 2-(benzyloxycarbonyl)benzene sulfonyl chloride were added thereto at 0° C. The mixture was stirred for 1 hour, then allowed to reach room temperature, and stirred for additional 24 hours. The reaction solution was extracted with ethyl acetate, washed with water, 1 N hydrogen chloride and saturated saline, and dried over powdery magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:8](O)[CH2:9][CH2:10][OH:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:8][CH2:9][CH2:10][O:11][CH:1]1[C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: OCCCO
Reactant: O=Cc1nccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(C2OCCCO2)n1
Temperature: 25 °C

Procedure:
A solution of 2-formylthiazole (10 g, 88 mmol), 1,3-propanediol (8 mL) and p-TsOH (100 mg) in benzene (110 mL) was heated at reflux temperature for 15 h with removal of water using a Dean-Stark apparatus. The mixture was cooled to room temperature and washed twice with sat. aq. NaHCO3, twice with water and concentrated. The resulting solid was crystallized from hexane to provide 2-(1,3-Dioxan-2-yl)thiazole as a tan solid (10.4 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH2:33])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1.O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH:33][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of pivaloyl chloride (34 mg; 0.28 mmol) in DCM (1 mL) was added dropwise to a mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide ((see Example 72, step (d)) 150 mg; 0.27 mmol), TEA (41 mg; 0.41 mmol) and DCM (2 mL) at 0° C. The resulting mixture was stirred over night at rt, poured into water and extracted with DCM. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O>CCO.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:8]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1ccc(Br)cc1N
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Br)cc1-n1c(C)ccc1C
Yield: 59.8 %

Procedure:
To a solution 5-bromo-2-methyl aniline (6.38 g, 36.74 mmol) in EtOH (30 ml) was added acetonyl acetone (5.0 ml, 42.62 mmol) and one drop of conc. aqueous HCl. The mixture was heated at reflux for 18 h and then cooled. Solvent was evaporated to dryness under reduced pressure and the residue was partitioned between water and EtOAc. The organic layer was separated and washed with water and brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/8:2) gave 5.8 g of 1-(5-bromo-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrole (60%) as a clear oil.