Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH:13]1([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:19]=[C:20]([NH2:22])[S:21][CH:2]=3)=[C:6]([CH3:18])[CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(N)=S
Reactant: Cc1cc(OC2CCCC2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OC2CCCC2)cc(C)c1-c1csc(N)n1
Yield: 73.5 %

Procedure:
A mixture of 2-bromo-1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (6.16 g, 19.8 mmol) and thiourea (1.51 g, 19.8 mmol) in 95% EtOH (28.3 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-(cyclopentyloxy)-2,6-dimethylphenyl)thiazol-2-amine (4.2 g) as white solids in 73.7% yield: 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 2 H), 6.24 (s, 1 H), 4.75 (m, 1 H), 2.13 (s, 6 H), 1.88-1.78 (m, 6 H), 1.62-1.59 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][C:33](C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH3:33])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: [Li]C(C)(C)C
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 1.6 mmol, Preparation #5, Step A) in THF (12 mL) was cooled to about −75° C. then t-BuLi (1.7 M in hexanes, 1.05 mL, 1.79 mmol) was added keeping the temperature about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. Additional t-BuLi (1.7 M in hexanes, 0.286 mL, 0.487 mmol) was added and the mixture was stirred an additional 15 min. The mixture was treated with MeI (0.461 g, 3.24 mmol) then the temperature of the mixture was raised to about 15° C. over about 10 min. The mixture was stirred at about 20° C. overnight then saturated aqueous NH4Cl (5 mL) was added. The mixture was stirred for about 15 min at about 20° C. then the material was partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography with a 25 g silica gel column and eluted with 0 to 40% EtOAc/heptane to provide 2-bromo-7-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.54 g, 66%): LC/MS (Table 2, Method g) Rf=2.25 min; MS m/z 504, 506 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.NC1CCCCO1.Cl>C(O)C.O>[O:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:24]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: NC1CCCCO1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (126.4 g, 0.68 mol) was dissolved in ethanol (880 mL). Triethylamine (82.6 g, 0.82 mol), 4-aminotetrahydropyran (82.7 g, 0.81 mol) were added in turn dropwise, and after the additions the reaction solution was heated to reflux. After refluxing for 5 h, triethylamine (8.3 g, 82 mmol), aminotetrahydropyran (8.3 g, 81 mmol) were added, and this was refluxed for a further 9 hours. After the reaction mixture was allowed to cool to room temperature, 2N HCl (880 mL) and water (880 mL) were added and after stirring for awhile, the solid obtained was filtered off. This was forced air-dried at 60° C. to yield the title compound (183.3 g, quant.) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([Cl:13])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:28]([C:11](=[O:12])[NH:10][CH2:8][CH3:9])[N:27]=1
Reactant: CCN=C=O
Reactant: COC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
Triethylamine (0.20 g, 2.0 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole-5-carboxylate (0.53 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (chloroform), to give a white solid of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-1 (N-ethylcarbamoyl)pyrazole-5-carboxylate (0.15 g, yield: 23.5%). mp: 88-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.3 Hz, 3H), 3.37 (dq, J=6.0 and 7.3 Hz, 2H), 3.95 (s, 3H), 6.21 (s, 1H), 6.40-6.60 (m, 1H), 7.68 (d, J=0.5 Hz, 2H).
Reaction SMILES: B.CSC.[CH:5]1([CH2:15][C:16](O)=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1>C1COCC1>[CH:5]1([CH2:15][CH2:16][OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: O=C(O)CC1OCCc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Borane-methyl sulfide (10.5 ml) in THF is added to an ice-cooled solution of (-)-(isochroman-1-yl)acetic acid (LXI, EXAMPLE 45--Step 3, 7.08 g, 36.8 mmol). After stirring for 20 min at 0°, the ice bath is removed and the solution is stirred at 20°-25° for another 1.7 hr. The reaction flask is then placed in an ice-water bath and methanol is added slowly until no further gas evolution occurs. The solvents are then removed under reduced pressure and methanol is again added and removed a second and third time. The residue is partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give (-)-2-(isochroman-1-yl)ethanol (LXXIX). This material is added to dimethylaminopyridine (0.22 g, 1.8 mmol), diisopropylethylamine (16.0 ml, 92 mmol) and THF (60 ml). The mixture is cooled in an ice-water bath and methanesulfonyl chloride (3.4 ml, 44.2 mmol) is added dropwise over several minutes. After stirring for 55 min at 0°, 4-(piperazin-1-yl)benzamide (IV, EXAMPLE 47 Step 1, 9.06 g, 44.2 mmol) and ethylene glycol (60 ml) are added. The mixture is heated at 80° overnight and then water is added and the resulting solid is collected and washed with water and toluene. After drying, the solid is passed through silica gel using methanol/dichloromethane (4/96) to give (-)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzamide, MS (m/z) 365; IR (mineral oil) 1610, 1239, 1643, 1112, 1622 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:15][C:16]#[C:17][CH3:18]
Reactant: CC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl- hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 g of the product was isolated. Yield 45%; white solid; mp 190° C.; MS: 377.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J=13.8 Hz, lH), 3.74 (d, J=13.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40 (m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3154 m, 3105 s, 3068 s, 2875 m, 1696 s, 1630 w, 1590 s;
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=C)=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].C[N+]1([O-])CC[O:26]CC1.CC(C)=O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[C:7]([CH:8]=[O:26])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reaction time: 16 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethenylpyrazole (0.1 g), N-methylmorpholine oxide (0.005 g), osmium tetroxide (5011 of a 2.5% solution in t-butanol) in water (5 ml) and acetone (45 ml) was stirred at room temperature for 16 hours Sodium metaperiodate (0.005 g) was added and stirring continued for 16 hours. The reaction mixture was evaporated and the residue partititoned between ether and aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a biege solid, m.p. 167.5-168.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].CON(C)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]>>[Cl:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: ClCc1ccccc1Cl
Reactant: CON(C)C(=O)c1ccc(I)cc1
Product: O=C(Cc1ccccc1Cl)c1ccc(I)cc1

Procedure:
The title compound was prepared from α,2-dichlorotoluene and O,N-dimethyl-4-iodobenzenehydroxamic acid (see Preparation 30) by a similar method to that of Preparation 20(i) as a colourless solid, m.p. 105-106° C., which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: CCCCCC.[H-].[Na+].[O:9]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[C:10]1[CH2:16][OH:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(OCC)C.O1CCCC1>[Si:18]([O:15][CH2:14][C:13]1[O:9][C:10]([CH2:16][OH:17])=[CH:11][CH:12]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1ccc(CO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)o1
Reaction time: 1 h

Procedure:
According to the method of P. G. McDougal, et al., J. Org. Chem., 51, 3388-3390 (1986), combine hexane washed sodium hydride (20 mmol) and tetrahydrofuran (40 mL). Slowly add 2,5-furandimethanol (20 mmol). After gas evolution ceases, add t-butyldimethylsilyl chloride (20 mmol) and stir vigorously. After about 1 hour, pour the reaction mixture into diethyl ether and extract with a saturated aqueous solution of sodium carbonate, water, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 5-(t-butyldimethylsilyloxy)methyl-2-hydroxymethylfuran. Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (10 mmol), 5-(t-butyldimethylsilyloxy)-methyl-2-hydroxymethylfuran (10 mmol), and triphenylphosphine (10 mmol) in tetrahydrofuran (100 mL). Add diethyl azodicarboxylate (10 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-4-(1-(5-(t-butyldimethylsilyloxy)-methylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.[F:26][C@H:27]1[C@H:31](OS(C)(=O)=O)[CH2:30][N:29]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[F:26][C@H:27]1[C@@H:31]([O:25][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([C:12]2[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=2)[CH:24]=[CH:23]3)[CH2:30][N:29]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:28]1
Reactant: CS(=O)(=O)O[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@H]5CN(C(=O)OCc6ccccc6)C[C@H]5F)c4n3)cnc2c1
Temperature: 100 °C

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (1.75 g, 5.22 mmol), (trans)-benzyl 3-fluoro-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (1.99 g, 6.3 mmol) and cesium carbonate (3.40 g, 10.4 mmol) were added to a sealed tube containing dimethylacetamide and heated to 100° C. overnight with stirring. The dimethylacetamide was removed under vacuum concentration and heat, chloroform was added, and this organic phase was gently washed with water. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel using a 6% solution of ammonium hydroxide in methanol and dichloromethane to yield three major products which could not be separated further by column purification (starting quinoline phenol, product and unidentified by-product). MS APCI (+) m/z 557.3 (M+1) detected. This crude material was taken directly on to the deprotection step.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.Cl[C:41]([O:43][CH3:44])=[O:42]>>[CH3:44][O:43][C:41]([C:7]1[N:8]([CH3:11])[N:9]=[C:10]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[Br:1])=[O:42]
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c2cccc(Br)c2nn1C
Temperature: 2.5 °C
Yield: 79.3 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me, 1.50 g, 7.12 mmol) in 50 mL of THE at −78° C. was added a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (4.3 mL, 8.6 mmol). The solution was stirred at 0-5° C. for 15 m, then rechilled to −78° C. To the solution was added methyl chloroformate (0.66 mL, 8.5 mmol) all at once, and the mixture was stirred while slowly warmed to room temperature over 19 h. The reaction was quenched with silica gel and concentrated. Column chromatography (0→20% EtOAc/hexanes) afforded of 7-bromo-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35a: 1.52 g; 79%; m.p. 131-132) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[CH2:8]([Br:11])[CH:9]=[CH2:10]>>[BrH:11].[CH2:10]([N:6]1[CH:5]=[C:4]([CH3:7])[S:3][C:2]1=[NH:1])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: Cc1cnc(N)s1
Product: Br
Product: C=CCn1cc(C)sc1=N

Procedure:
A mixture of 2-amino-5-methylthiazole (2.5 g) and allylbromide (3.31 g) was processed according to the method of Example 227A to afford the title compound that was taken directly to the next step. MS (ESI+) m/z 155 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]4[CH:26]=[C:27]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:28]=[CH:29][C:20]=4[C:19]=3[C:18]3[C:36]([CH3:48])=[N:37][N:38](CC4C=CC(OC)=CC=4)[C:17]=3[N:16]=2)=[CH:11][C:10]=1[C:49]([F:52])([F:51])[F:50])C1C=CC=CC=1.C(OC(C)C)(C)C.[ClH:60].O1CCOCC1>FC(F)(F)C(O)=O>[ClH:60].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]4[CH:26]=[C:27]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)[CH:28]=[CH:29][C:20]=4[C:19]=3[C:18]3[C:36]([CH3:48])=[N:37][NH:38][C:17]=3[N:16]=2)=[CH:11][C:10]=1[C:49]([F:52])([F:51])[F:50]
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OCc6ccccc6)c(C(F)(F)F)c5)nc32)c(=O)[nH]c2cc(N3CCNCC3)ccc24)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)c(C(F)(F)F)c3)c3c(=O)[nH]c4cc(N5CCNCC5)ccc4c3c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A solution of 1.8 g (2.55 mmol) of 5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-3-(4-methoxybenzyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one dissolved in 25 ml of trifluoroacetic acid is carried at 70° C. for 3 hours. After returning to room temperature, 50 ml of diisopropyl ether is added until a stable precipitate appears; the latter is filtered and then taken up in water. Acidity is neutralized by the addition of 1 M soda. The solid is filtered again and then triturated several times in hot methanol to yield after a final filtration 950 mg of 5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one. The product is then taken up in 20 ml of anhydrous dioxane; a 4 M solution of hydrochloric acid in dioxane (932 μl, 3.73 mmol) is added and the reaction medium is stirred at room temperature for 2 hours. The precipitate is filtered, rinsed with dioxane and triturated in methanol to yield 475 mg (36%) of 5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrochloride in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[S:8][C:9]3[C:10](=[N:11][CH:12]=[C:13]([C:23]#[N:24])[C:14]=3[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C=O>[Br:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:14]1[C:13]([C:23]#[N:24])=[CH:12][N:11]=[C:10]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:25](=[O:28])[CH:26]=[CH2:27])[C:7]=3[S:8][C:9]=12
Reactant: C=CC(=O)O
Reactant: N#Cc1cnc2c(sc3c(N)cccc32)c1Nc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc2c1sc1c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 43 %

Procedure:
A 0.138 g (0.349 mM) portion of 6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile is dissolved in 2 mL of tetrahydrofuran and 2 mL of dimethylformamide at 0° C. To this is added 0.042 g (0.583 mM) of acrylic acid, 0.105 g (0.575 mM) of N,N-diisopropylethylamine and 0.106 g (0.554 mM) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride with stirring under nitrogen. The reaction mixture is stirred for 48 hours at room temperature, and the solvent is removed under reduced pressure. The residue is worked up with water (3 mL) and extracted with methylene chloride (10 mL), dried with sodium sulfate and evaporated. Purification of the product is carried out by silica get chromatography, eluting with 20:1 chloroform/methanol. Further purification is achieved by preparative thin layer chromatography, eluting with the same solvent system. Finally, the product is washed with ether to provide 0.068 g (43%) of N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide, m.p. 286–287° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:11][CH2:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: CCc1cccc(N2CCNCC2)c1
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cccc(N2CCN(C(=O)Cc3ccccc3OCC(F)(F)F)CC2)c1
Reaction time: 48 h

Procedure:
1-(3-ethylphenyl)piperazine from the previous step was dissolved in 1 mL dry DMF, and to the solution was added 0.03 g (0.128 mmol) 2-(2,2,2-trifluoroethoxy)phenylacetic acid, 0.017 g (0.128 mmol) HOBT, and 0.024 g (0.128 mmol) EDC. The reaction was stirred for 2 days, after which time the solvent was removed in vacuo and the resulting residue partitioned between EtOAc/H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, brine, dried over Na2SO4 and filtered. Removal of the solvent and subsequent purification via preparative TLC (2:1 Hexane/EtOAc) yielded the title compound as the free base. This was dissolved in 20 mL EtOAc and an excess of ethanolic HCl was added. The solvent was removed to give the Hcl salt of the title compound.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:26]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](=[O:17])[NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH:8]1[C:6]([OH:7])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)N(Cc3ccccc3)Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)N(Cc3ccccc3)Cc3ccccc3)C2C(=O)O)cc1

Procedure:
3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (200 mg, 0.33 mMol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1) to afford the free acid: Cal. 550.6 found (M)+=550.