Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13]3)[CH:10]=2)[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=1.[CH:20]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13]4)[CH:10]=3)[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=2)[CH2:21][CH2:22]1
Reactant: Cc1cnn(-c2ccc3c(=O)n(C)cc(Br)c3c2)c1
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnn(-c2ccc3c(=O)n(C)cc(-c4cc(S(C)(=O)=O)ccc4OCC4CC4)c3c2)c1
Yield: 25.7 %

Procedure:
4-Bromo-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (40.0 mg, 0.126 mmol), the title compound of Example 90, step 1 (53.2 mg, 0.152 mmol), Pd(dppf)Cl2 (200.0 mg, 0.05 mmol) and aqueous 1M K3PO4 (0.38 mL, 0.38 mmol) in dioxane (3 mL) were heat in a microwave at 100° C. for 1 h. Purification by preparative HPLC gave the title compound (15.0 mg, 25%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.57 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 7.12 (s, J=9.2 Hz, 1H), 3.96-3.83 (m, 2H), 3.68 (s, 3H), 3.13 (s, 3H), 2.15 (s, 3H), 1.01-0.94 (m, 1H), 0.38-0.28 (m, 2H), 0.08-0.02 (m, 2H). LCMS: 464.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][C:3]=1[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18]
Reactant: COC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(Cl)c(CNC(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl N-[[2-chloro-5-[2-(trimethylsilyl)ethynyl]phenyl]methyl]-carbamate (i.e. the product of Step C) (1.37 g, 4.6 mmol) in methanol (28 mL) was added potassium hydroxide (2.3 mL, 1M in methanol). The reaction mixture was stirred at room temperature for 18 h, and then concentrated. The resulting residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a brown oil (0.90 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[N:28]=[N:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[CH3:22][C:23]1[N:28]=[N:27][C:26]([N:29]2[CH2:32][CH:31]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@@H:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]4)=[CH:20][CH:21]=3)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: Cc1ccc(N2CC(C(=O)O)C2)nn1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(O[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc3)C2)nn1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-(4-aminophenoxy)pyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 1-(6-methylpyridazin-3-yl)azetidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3.ClC1C=CC=C(C(OO)=[O:23])C=1>>[CH3:1][S:2]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)C(=O)C1(CC1)O2
Product: CS(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 76.3 %

Procedure:
5-Methylthiospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (600 mg.) and m-chloroperbenzoic acid (627 mg.) were allowed to react in the same manner as Example 65. The product was recrystallized from ethyl acetate-hexane to give colorless prisms of 5-methylsulfinylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (493 mg.). m.p. 87°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:9][C:5]1[C:6]([O:8][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 13 h
Yield: 72 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorophenol (5.00 g, 30.9 mmol), 2-chloro-5-nitropyridine (5.09 g, 32.1 mmol), potassium carbonate (4.51 g, 32.6 mmol) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 13 hr. To the reaction mixture was added aqueous ammonium chloride solution (50 mL), and the mixture was extracted with ethyl acetate (80 mL×3). The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (6.31 g, 72%) as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])[C:4](OCC)=[O:5].C[Si](C)(C)N[Si](C)(C)C>>[Si:12]([O:11][C@@H:9]([C@@H:3]1[CH2:2][NH:1][C:4]1=[O:5])[CH3:10])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H](CN)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Temperature: 70 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
A mixture of ethyl (2S,3R)-2-aminomethyl-3-(t-butyldimethylsilyloxy)butanoate (1.38 g) and 1,1,1,3,3,3-hexamethyldisilazane (1.58 ml) was stirred at 70° C. for 15 hours, and then concentrated under reduced pressure. The residue was dissolved in 50 ml of tetrahydrofuran and 1.1N t-butylmagnesium chloride in tetrahydrofuran (15 ml) was added dropwise thereto at room temperature. After stirring for 30 minutes, the reaction mixture was quenched with water (10 ml), and diluted with ethyl acetate (50 ml) and 1N hydrochloric acid in water (20 ml). The aqueous layer was separated and extracted twice with ethyl acetate (25 ml×2) and the combined organic layers were washed in turn with 1N hydrochloric acid in water (20 ml), saturated sodium bicarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was column-chromatographed on silica gel (hexane-ethyl acetate=3:1) to give (3S)-3-[ (1R)-1-(t-butyldimethylsilyloxy)ethyl]-azetidin-2-one (0.841 g).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1([CH3:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C>CCO.[OH-].[Na+]>[CH3:13][C:7]1([CH:6]=[CH:5][C:4]([OH:14])=[O:3])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C=CC1(C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C=CC(=O)O)CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-methyl-tetrahydro-pyran-4-yl)-acrylic acid ethyl ester (396 mg, 2.00 mmol, prepared as in STEP A above) in EtOH (10 mL), 6N aqueous NaOH (1 mL) was added dropwise. The resulting mixture was stirred at room temperature over night. The resulting mixture was concentrated and the resulting residue was dissolved in 20 mL of water. The resulting solution was washed twice with diethyl ether (10 mL), and the aqueous layer was acidified with 6N HCl and extracted thrice with DCM (20 mL). The DCM layers were combined, dried over Na2SO4 and concentrated in vacuo to yield 3-(4-methyl-tetrahydro-pyran-4-yl)-acrylic acid, which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12](OC)=[O:13])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:18][N:19]=[C:20]=[O:21].C[O-].[Na+]>CO>[CH3:18][N:19]1[C:12](=[O:13])[CH2:11][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[NH:10][C:20]1=[O:21]
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN(c2cccc(C(F)(F)F)c2)NC1=O

Procedure:
Methyl [1-[3-(trifluoromethyl)phenyl]hydrazino]acetate (5 g) was treated with methyl isocyanate (3.05 ml) and then with sodium methoxide in methanol (60 ml; from sodium (1.16 g)) according to the method of Example 1. The product was purified by FCC eluting with System A (19:1) to give a solid, which was crystallised from System B to give the title compound (1.3 g), m.p. 163°-165°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].O.Br[C:9]1[N:13]([C:14]2[C:22]3[C:18](=[N:19][O:20][N:21]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[N:11][N:10]=1>C(Cl)(Cl)Cl>[N:19]1[O:20][N:21]=[C:22]2[C:14]([N:13]3[C:12]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[N:11][N:10]=[C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:15][CH:16]=[CH:17][C:18]=12
Reactant: Brc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Reactant: CNCCOC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Temperature: 160 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) and water (3 ml) were added to 4-[3-bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazol (336 mg) prepared in the Production Example 5, and stirred at 160° C. for 6 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from ethyl acetate, to afford the entitled compound as white crystal (66 mg, 19%). The physico-chemical values are as follows.
Reaction SMILES: C(C(CCCC)COC(=O)C[CH2:8][S:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:16]3[N:17]2[CH:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=1)C.N#N.CC(C)([O-])C.[K+].[CH3:42][O:43][C:44]([C:46]1([C:52]2[CH:57]=C[CH:55]=[C:54](Br)[CH:53]=2)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[CH3:42][O:43][C:44]([C:46]1([C:52]2[CH:53]=[CH:54][CH:55]=[C:8]([S:9][C:10]3[CH:19]=[C:18]4[C:13]([C:14]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:15][C:16]5[N:17]4[CH:20]=[CH:21][N:22]=5)=[CH:12][CH:11]=3)[CH:57]=2)[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1)=[O:45]
Reactant: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nccn3c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2cccc(Sc3ccc4c(-c5ccccc5)cc5nccn5c4c3)c2)CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1x (200 mg, 0.43 mmol) in 1,4-dioxane (5 mL) was degassed with N2 for 10 minutes and cooled to 0° C. Potassium tert-butoxide (73 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. The solution was degassed with N2 for another 5 minutes while 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (1y, 130 mg, 0.43 mmol), Pd2dba3 (10 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg, 0.02 mmol), and iPr2NEt (0.15 mL, 0.87 mmol) were added. The reaction was heated to 60° C. overnight, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 1z.
Reaction SMILES: C[C:2]1[C:3]([CH:13]2[CH2:16][N:15]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14]2)=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1>N1C=CC=CC=1.C(Cl)Cl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:23][C:24]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]3[C:27]([CH:28]4[CH2:38][CH:29]4[CH2:30][O:31]3)=[CH:26][CH:25]=2)(=[O:10])=[O:11])=[C:3]([CH:13]2[CH2:14][N:15]([C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:16]2)[CH:2]=1
Reactant: Cc1c(F)ccc(S(=O)(=O)Cl)c1C1CN(C(=O)C(F)(F)F)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CN(C(=O)C(F)(F)F)C2)ccc2c1OCC1CC21
Reaction time: 18 h
Yield: 104.2 %

Procedure:
A solution of methyl 4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzenesulfonyl chloride (Intermediate 89, 0.192 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.122 g) in pyridine (1 mL) and DCM (3 mL) was left to stand at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1M hydrochloric acid and filtered through a phase separator. 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 0-30% to give methyl (1aRS,7bSR)-5-{4-fluoro-2-[1-(2,2,2-trifluoro-acetyl)azetidin-3-yl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.294 g) as a colourless gum.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24].CCOC(C)=O>CN(C=O)C>[O:24]=[C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:22][NH:14][C:9]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CBr)N1CCCCc2ccccc21
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1Nc1ccccc1)N1CCCCc2ccccc21
Yield: 99.2 %

Procedure:
To a stirring solution of N-phenyl-o-phenylene diamine (10 g, 54.3 mM) in 100 ml of DMF at RT was added K2CO3 (8.25 g, 60 mM) followed by 1-(bromoacetyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (14.56 g 54.3 mM). The resulting mixture was stirred at RT until TLC (Hex:AcOEt 3:1) showed completion of reaction. The mixture was filtered to remove the K2CO3 and then diluted with 800 mL of EtOAc and 200 mL of Et2O. This solution was washed successively with H2O (2×400 mL), brine (1×400 mL), 1 N HCl (2×400 mL), and H2O (1×400 mL), and the organics dried (MgSO4) and concentrated to give a greenish-black oil. The resultant oil was purified by silica gel flash column chromatography using hexane/EtOAc4/1 and the combined filtrates evaporated in vacuo to give 20 g of product. 1H NMR (300 MHz, CDCl3) 1.25–1.40 (m, 1H), 1.66–2.00 (m, 3H), 2.55.2.75 (m, 2H), 2.88 (t, J=13 Hz, 1H), 3.54(d, J=17 Hz, 1H), 4.10 (d, J=17 Hz, 1H), 4.57 (m, 1H), 6.80–7.80 (m, 12H), 7.47 (m, 1H).
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C(F)(F)C([O:9][C:10](=O)[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=O>FC(F)(F)C(F)(F)C(F)(F)C(O)=O>[F:17][C:12]([F:18])([C:13]([F:14])([F:15])[F:16])[C:11]([F:20])([F:19])[C:10]([O:1][O:2][C:10](=[O:9])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])=[O:9]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OO
Agent: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with heptafluorobutyric anhydride to give bis(heptafluorobutanoyl) peroxide (δ−82.6, −118.4, −128.2) in heptafluorobutyric acid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[CH:5](O)[C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[CH:9][C:10]=1[N+:11]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:4]1[C:3](=[O:2])[NH:11][C:10]2[CH:9]=[N:8][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:5]=1
Reactant: COC(=O)C(Oc1ccc(F)cc1F)C(O)c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(=O)c(Oc3ccc(F)cc3F)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-3-hydroxy-3-[4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]propionic acid methyl ester (125 mg, 0.264 mmol) in ethanol (2 mL) and water (1 mL) was added ammonium chloride (74 mg, 5.2 eq) followed by iron powder (Fisher Brand, Electrolytic). The resulting mixture was stirred at room temperature for 45 minutes, refluxed overnight, cooled to room temperature, diluted with ethanol, and filtered through a 3 cm bed of celite with additional ethanol. The filtrate was concentrated, and the residue was diluted with ethyl acetate (80 mL) and water (40 mL). The organic layer was separated, washed with water (2×40 mL) and brine (1×40 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a thick tan oil (98 mg, (M+H)+=394).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(OCC)C>[CH2:15]([O:14][C:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCOCC
Product: CCOC(=O)c1cn2cc(F)ccc2n1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-fluoropyridine (1.12 g) in diethyl ether (25 ml) was added ethyl bromopyruvate (1.25 ml). the mixture was stirred for 1 hour. The resultant solid was filtered off, suspended in ethanol and heated at reflux for 4 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate solution (100 ml). The organic layer was separated, dried, (magnesium sulfate) and the solvent removed by evaporation. The residue was purified by flash chromatography (silica) eluting with ethyl acetate:hexane (3:1) to give the sub-title compound as a colourless solid (1.12 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O1CCCC1.CO>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(\C)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
Compound 19a (929 mg), iron powder (1.97 g), and ammonium chloride (436 mg) were added to a mixed solution of tetrahydrofuran (4 ml), methanol (4 ml), and water (4 ml). The obtained mixture was stirred at 70° C. for 3.5 hours. The mixture was allowed to cool and then filtered. The filtrate was separated with ethyl acetate and water. The organic layer was sequentially washed twice with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (17%-33% ethyl acetate/n-hexane) to obtain Compound 19b (757 mg, 96%) as an orange solid. 1H-NMR (CDCl3) δ7.35 (2H, d, J=8.7 Hz), 6.65 (2H, d, J=8.7 Hz), 6.09 (1H, s), 4.19 (2H, q, J=7.1 Hz), 3.85 (2H, brs), 2.54 (3H, s), 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CN1CCN(C(=O)c2cncc(Cl)n2)CC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (70 mg, 0.287 mmol, 1 eq) and (6-chloropyrazin-2-yl)(4-methylpiperazin-1-yl)methanone (60) (69 mg, 0.287 mmol, 1.0 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (140 mg, 0.430 mmol, 1.5 eq) followed by addition of Pd(dpp)Cl2 (13.2 mg, 0.0114 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1-2% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(4-methylpiperazin-1-yl)methanone 139 in 20 mg quantity. The compound 139 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.98 (s, 1H), 9.45 (s, 1H), 9.04 (d, J=1.95, 1H), 8.76 (m, J=12.43, 2H), 7.63 (m, J=2.68, 1H), 6.64 (m, J=1.58, 1H), 3.76 (s, 2H), 3.59 (m, J=69.03, 2H), 2.42 (m, 4H), 2.28 (s, 3H); MS m/z 321.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]3)[C:15]=2[N:14]=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Br.[NH2:63][C:64]1[NH:65][CH2:66][CH2:67][CH2:68][N:69]=1>CN(C=O)C>[C:6]1([CH:5]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([NH:63][C:64]5[NH:69][CH2:68][CH2:67][CH2:66][N:65]=5)=[O:29])[CH2:25][CH2:26]4)[C:15]=3[N:14]=[CH:13]2)[CH2:4][C:3]([O:2][CH3:1])=[O:30])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)O)CC3)cccc21
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)NC4=NCCCN4)CC3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[1-(3-methoxy-3-oxo-1-phenylpropyl)-1H-benzimidazol-4-yl]-4-piperidinecarboxylic acid (70 mg, 172 μmol) in DMF was added N,N-diisopropylethylamine (60 μL, 344 μmol) and TBTU (66 mg, 206 μmol). The solution was stirred at room temperature for 0.5 hour, then 2-amino-1,4,5,6-tetrahydropyrimidine hydrobromide (34 mg, 189 μmol) was added. The mixture was heated to 80° C. for 8 hours, cooled to room temperature, and evaporated in vacuo. The residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.66 min, MH+ 489].