Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[Na].[N-:22]=[N+:23]=[N-:24].[Na+].CNCCNC>CS(C)=O.O.[Cu](I)I>[N:22]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)=[N+:23]=[N-:24]
Reactant: Nc1ccc(I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(N)cc1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
4-iodoaniline (400 mg, 1.8263 mmol) was mixed with sodium L-ascorbic acid (90 mg, 0.46 mmol) in DMSO (25 mL). A solution of sodium azide (241 mg, 3.65 mmol) in water (6.5 mL) was added followed by N,N′-dimethylethane-1,2-diamine (30 mg, 0.4 mmol) and copper iodide (30 mg, 0.2 mmol). The mixture was then heated at 100° C. for 6 h. The mixture was then mixed with a large amount of water (80 mL) and then extracted with EtOAc (3 times). The organics were dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography (silica, eluting with MeOH in DCM) to give 4-azidoaniline (150 mg). 1H NMR (400 MHz, DMSO) δ 6.81-6.75 (m, 2H), 6.63-6.57 (m, 2H), 5.13 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:21][O:20][CH2:19][CH2:18][N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:5][CH2:6]1
Reactant: COCCBr
Reactant: c1cc2[nH]ncc2cc1OC1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCC(Oc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of the 5-(4-piperidinyloxy)-1H-indazole (100 mg, 0.460 mmol) obtained in Example 42 in N,N-dimethylformamide (3 ml) were added (2-bromoethyl)methyl ether (76.8 mg, 0.552 mmol) and potassium carbonate (159 mg, 1.15 mmol), and the resulting mixture was stirred overnight at room temperature. Then, the reaction solution was cooled to 0° C. and a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 5-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-1H-indazole (52 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(Cl)Cl>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ccc(C3CC3)cn2)c1C
Temperature: 110 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A suspension of 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (18 g) described in Reference Example 24 (2), cyclopropylboronic acid (9.96 g), dichlorobis(tricyclohexylphosphine)palladium (II) (2.14 g) and tripotassium phosphate (49.2 g) in 1,4-dioxane (120 ml) was stirred at 110° C. for 3 hours. After completion of the reaction, the mixture was allowed to cool, chloroform was added thereto, filtered through Celite, then, to the filtrate was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (14 g) as a yellow solid. MS (ESI) m/z: 272 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]O)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[Br:30]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Br:30])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCBr)[C@H]1Oc1ccccc1
Reaction time: 1.17 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (700 mg, 1.718 mmol) in CH2Cl2 (17 mL) at 0° C. (icewater bath) were added perbromomethane (627 mg, 1.890 mmol) and triphenylphosphine (541 mg, 2.061 mmol). After 70 min, TLC (2:1 hexanes:acetone) showed incomplete conversion so additional CBr4 and Ph3P (64 mg and 54 mg, respectively) were added and the reaction was stirred for an additional 20 min. The reaction was concentrated and purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a hard white foam (712 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 2H), 7.03-6.82 (m, 3H), 5.18-4.99 (m, 2H), 4.21 (q, J=8.7 Hz, 2H), 3.44 (ddd, J=10.0, 7.4, 5.0 Hz, 1H), 3.33 (ddd, J=9.9, 8.4, 6.9 Hz, 1H), 2.28 (dt, J=13.0, 6.6 Hz, 1H), 2.10 (dtd, J=12.6, 7.9, 4.5 Hz, 1H), 2.05-1.96 (m, 1H), 1.85-1.73 (m, 2H), 1.73-1.61 (m, 1H), 1.44 (s, 10H), 1.30 (d, J=6.5 Hz, 3H), 1.28-1.20 (m, 1H), 1.20-1.09 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.20, 159.18, 154.89, 129.74, 121.33, 115.37, 80.94, 79.95, 74.57, 53.02, 41.18, 34.13, 33.95, 31.54, 28.33, 19.13, 18.29; HRMS-ESI (m/z) ([M+Na]+) calcd for C22H32BrNNaO5, 492.1356; found, 492.1352.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1cccc(F)c1
Reactant: ClCCOCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 165.3 %

Procedure:
Potassium tert-butoxide (5.48 g, 48.8 mmol) was added to a stirred solution of 2-(3-fluorophenyl)acetonitrile (2.58 mL, 22.2 mmol) in DMF (30 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (2.86 mL, 24.4 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (7.53 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[S:27]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28]1>>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([NH:33][CH2:32][C:29]5[CH:30]=[CH:31][S:27][CH:28]=5)[N:10]=4)=[CH:12][N:13]=3)[CH:16]=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: NCc1ccsc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and thiophen-3-ylmethanamine (145 mg, 1.28 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford {4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine (Yield 69 mg, 52.8%). 1H NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.35 (d, 1H, J=5.4 Hz), 7.94 (t, 1H, J=5.7 Hz), 7.51-7.34 (m, 3H), 7.20-7.12 (m, 2H), 4.56 (d, 2H, J=5.7 Hz), 4.17 (brs, 4H), 2.52-2.44 (m, 4H), 2.23 (s, 3H). LC-MS: [M+H]+ 407.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[C:4]([N:5]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cccc(Br)c1F)S(C)(=O)=O
Reaction time: 2 h

Procedure:
A solution of 3-bromo-2-fluoroaniline (Intermediate 34-1, 160 mg, 0.842 mmol) and DIEA (0.368 mL, 2.105 mmol) in DCM (3 mL) was stirred at ca. −5° C. and treated with methanesulfonyl chloride (0.098 mL, 1.263 mmol) and stirred at that temperature for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)-N-(methylsulfonyl)methanesulfonamide as a yellow solid (308 mg, quantitative), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, ddd, J=8.1, 6.4, 1.5 Hz), 7.33 (1H, ddd, J=8.1, 6.5, 1.6 Hz), 7.15 (1H, td, J=8.1, 1.4 Hz), 3.46 (6H, s). Mass spectrum m/z 363, 365 (M+NH4)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][N:8]=1)[NH2:3].O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:3][NH:2][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][N:8]=1)(=[O:19])[CH3:18]
Reactant: Cc1ccccc1-c1nnc(NN)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NNc1nnc(-c2ccccc2C)s1
Reaction time: 0.5 h

Procedure:
A solution of 2-hydrazino-5-(2-methylphenyl)-1,3,4-thiadiazole hydrochloride (1.0 g) in a mixture of acetic anhydride (0.5 ml) and pyridine (0.5 ml) was kept at room temperature under nitrogen for 0.5 hr. The solution was poured into water (100 ml) and extracted three times with methylene chloride. The organic layer was evaporated and the residue was fractionated on two 20 × 20 cm, 2 mm thick silica preparative t.l.c. plates by eluting with chloroform-methanol (4:1). The resultant product was crystallised from ethyl acetate (0.32 g; 31%) m.p. 165°-6°. C11H12N4OS requires C, 52.8; H, 5.6; N, 22.4; S, 12.8 Found C, 52.8; H, 5.1; N, 22.8; S, 13.2%
Reaction SMILES: S(O[CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:25][NH2:26].C(OCCO)C.C(=O)(O)[O-].[Na+]>>[CH3:25][NH:26][CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC2CCc3[nH]c4ccccc4c3C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Product: CNC1CCc2[nH]c3ccccc3c2C1
Reaction time: 8 h

Procedure:
A mixture of 17 g. of 3-tosyloxy-1,2,3,4-tetrahydrocarbazole and 25 g. of 40% methylamine in 200 ml. of 2-ethoxyethanol containing 5 g. of sodium bicarbonate was heated on a steam bath for one hour then left standing overnight at room temperature. The solvent was removed by distillation and the residue taken up in ether and the mixture filtered. Evaporation of the filtrate gave a residue which crystallized upon trituration with ether. The 3-(methylamino)-1,2,3,4-tetrahydrocarbazole thus obtained melted at 134°-136° C. (corr.).
Reaction SMILES: B(Br)(Br)Br.[C:5]1([CH2:11][CH2:12][C:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22]C)=[CH:21][C:16]=3[O:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([CH2:11][CH2:12][C:13]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc2c(CCc3ccccc3)coc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred, −10° C. solution of the product from Step B (2.066 grams; dry methylene chloride; 20 mL) was treated with 1M boron tribromide solution (methylene chloride; 8.40 mL). After 15 minutes, the reaction was warmed to ambient temperature and stirred another 15 minutes. It was partitioned between isopropyl acetate and pH7 phosphate buffer, then washed twice more with pH7 buffer and dried over magnesium sulfate. Filtration and evaporation produced an oil which was chromatographed over silica gel (step gradient; CH2Cl2 to 40:1 CH2Cl2/ethyl acetate). The title compound was isolated as a pale yellow solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)=[O:11])=[C:8]([F:25])[C:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:6][CH:5]=1.O>O1CCOCC1>[Cl:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[O:11])=[C:8]([F:25])[C:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Yield: 32 %

Procedure:
Lithium hydroxide monohydate (12 mg, 0.281 mmol) was added to a solution of ethyl (4-{[(6-chloro-3-{[(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}phenyl)acetate (91 mg, 0.192 mmol in dioxane (2 ml) and water (1 ml) and the reaction was stirred at room temperature overnight. The solvent was evaporated, the residue dissolved in water (5 ml) and acidified (2M HCl, pH˜1). The aqueous layer was extracted with ethyl acetate, the organics dried (Na2SO4) and the solvent evaporated to afford a colourless solid which was collected by filtration. This was purified by mass directed auto-prep (MDAP) to afford the title compound as a colourless solid (28 mg, 32%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[C:18](#[N:21])[CH:19]=[CH2:20]>O1CCCC1>[C:18]([CH2:19][CH2:20][C:5]1([C:3](=[O:4])[NH:2][CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:21]
Reactant: C=CC#N
Reactant: CNC(=O)C1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)C1(CCC#N)c2ccccc2-c2ccccc21

Procedure:
A 36.8 g. portion of 9-(N-methylcarbamoyl)fluorene was reacted with 10.6 g. of acrylonitrile in the presence of 10 g. of Triton B in tetrahydrofuran as described in Example 4. The reaction mixture was then concentrated under vacuum to a semi-solid, which was added to ice-water/ethyl acetate. The organic layer was separated, washed with water, and dried over sodium sulfate. The solution was evaporated to dryness to obtain 45.8 g. of crude product, which was crystallized from ethyl acetate/hexane to obtain 30 g. of the desired product, m.p. 185°-187°. Infrared analysis of the product showed a carbonyl band at 1685 cm-1 and a nitrile band at 2270 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][C:9]3[C:10]([C:24]([OH:26])=O)=[CH:11][N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:27]1[N:31]=[CH:30][N:29]([C:32](N2C=NC=C2)=O)[CH:28]=1>C(#N)C>[CH3:30][N:29]([CH3:32])[CH2:28][CH2:27][NH:31][C:24]([C:10]1[C:9]2[N:8]=[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]=1)=[O:26]
Reactant: Cc1cccc2cc3c(=O)n(Cc4ccccn4)cc(C(=O)O)c3nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cccc2cc3c(=O)n(Cc4ccccn4)cc(C(=O)NCCN(C)C)c3nc12
Yield: 75 %

Procedure:
From acid 18t, with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a bright yellow solid (75%), mp 183-184° C., (from acetonitrile). 1H NMR (CDCl3): δ 2.25 [s, 6H, N(CH3)2], 2.57 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.67 (s, 3H, ArCH3), 3.66 (q, J=6.1 Hz, CH2, CH2CH2NMe2), 5.30 (s, 2H, CH2Pyr), 7.10 (dd, J=7.0, 5.2 Hz, 1H, H-5′), 7.26-7.33 (m, 2H, H-3′, H-8), 7.52-7.59 (m, 2H, H-4′, H-7), 7.64 (d, J=8.2 Hz, 1H, H-9), 8.46 (d, J=4.4 Hz, 1H, H-6′), 8.66 (s, 1H, H-3), 9.02 (s, 1H, H-10), 10.79 (br t, J=5.1 Hz, 1H, CONH). 13C NMR (CDCl3): δ 18.3 (ArCH3), 37.3 (CH2CH2NMe2), 45.2 [N(CH3)2], 53.7 (CH2Pyr), 58.6 (CH2CH2NMe2), 109.6 (C-4), 119.1 (C-10a), 122.1 (CH, C-3′), 122.7 (CH, C-5′), 125.5 (C-9a), 126.4 (CH, C-8), 127.0 (CH, C-9), 132.6 (CH, C-7), 135.6 (C-6), 136.7 (CH, C-4′), 139.6 (CH, C-10), 143.4 (CH, C-3), 147.7 (C-5a), 148.5 (C-4a), 149.6 (CH, C-6′), 155.0 (C-2′), 162.2 (C-1), 164.3 (CONH).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:36]=[CH:35][C:19]3[NH:20][C:21]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:18]=3[CH:17]=2)[CH2:9][O:8]1)(C)(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1>[OH:8][CH2:9][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:36]=[CH:35][C:19]2[NH:20][C:21]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)OC1(c2ccccc2-c2ccc3[nH]c(COc4ccc(C(F)(F)F)cc4)nc3c2)CO1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A reaction mixture of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-oxiranyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.072 g, 0.134 mmol) and toluenesulfonic acid monohydrate (0.031 g, 0.161 mmol) in THF (2 mL) was heated to 80° C. and stirred for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a brown oil (0.053 g, 92%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64 (d, 2H, J=9.2 Hz), 7.62-7.56 (m, 2H), 7.54-7.46 (m, 4H), 7.26-7.23 (m, 3H), 5.45 (s, 2H), 4.06 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H18F3N2O3: 427.4 (M+H), Found 427.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
0.28 g of picolic acid (2.32 mmol) and 0.8 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.32 mmol) were dissolved in 30 ml of dichloromethane. After addition of 1.19 g of diisopropylethylamine (9.26 mmol), 0.155 g of hydroxybenzotriazole (HOBt, 1.15 mmol), and 0.487 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.54 mmol) at 0° C., the reaction mixture was stirred for 16 h at room temperature. 0.24 g of N-Ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 5 h. 100 ml of dichloromethane were added. The organic layer was washed twice with water. The dichlormethane phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate as eluent. The residue was re-dissolved in 15 ml of diethylether and treated with 1 N hydrochloric acid in diethyl ether. The precipitate was collected by filtration to yield 0.95 g of the title compound as a hydrochloride salt.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:31]I>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH3:31])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Product: COCc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and methyl iodide. Colorless crystals (190 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:40][OH:41]>>[OH:41][NH:40][C:37]([C@@H:10]1[C@H:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:39]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.17 g, 0.30 mmol) and hydroxylamine gave a 7:1 mixture of cis- and trans-tert-Butyl (3S,4R)-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1-carboxylate as an amorphous white solid (0.025 g, 14.6%) after purification using Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. Mass Spectrum Found: 571 (M+H)+
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1[S:23][C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[C:25]([Br:27])[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1[S:23][C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[C:25]([Br:27])[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1nccc1-c1sc(C(=O)NC(CCN(C(=O)[O-])C(C)(C)C)Cc2ccccc2)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1sc(C(=O)NC(CCN)Cc2ccccc2)cc1Br
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate (130 mg, 0.24 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.