Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14](S(C)(=O)=O)[C:15]2[N:16]([C:18]([C:21]3[CH:32]=[CH:31][C:24]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])=[C:23]([CH3:33])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1>CS(C)=O>[Br:11][C:12]1[CH:13]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[C:15]2[N:16]([C:18]([C:21]3[CH:32]=[CH:31][C:24]([C:25](=[O:26])[NH:27][CH:28]4[CH2:30][CH2:29]4)=[C:23]([CH3:33])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1
Reactant: NCCCS(=O)(=O)O
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cnc3c(NCCCS(=O)(=O)O)cc(Br)nn23)ccc1C(=O)NC1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 41 mg (300 μmol) 3-aminopropane-1-sulfonic acid in 2 mL DMSO is added 24 mg (600 μmol) sodium hydride at rt. After 30 min, 90 mg (200 μmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide are added which was prepared according to intermediate example 516b to give after stirring for 2 h, the crude title compound which was used after evaporation of the solvent without further workup.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1C(=O)N([I:23])C(=O)C1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=1>OS(O)(=O)=O>[Cl:24][C:25]1[CH:26]=[C:27]([O:34][CH3:35])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][C:30]=1[I:23]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.9 %

Procedure:
To a solution of H2SO4 (600 mL, 90%), trifluoromethanesulfonic anhydride (11.3 g, 0.04 mol) and NIS (49.68 g, 0.22 mol) were added and resulting mixture was stirred at room temperature for 1 h. To this mixture, 4-chloro-2-methoxy-1-nitrobenzene (69 g, 0.368 mol) was added quickly. The mixture was stirred for 1 h, and then NIS (33.12 g, 0.148 mol) was slowly added to the mixture. The mixture was stirred at room temperature for 1 h and then was poured into ice-water. The precipitate collected by filtration, rinsed with water, aqueous NaSO3 and NaHCO3 solutions, and then dried in vacuo to afford the desired product (113 g, 98% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH:20]([CH3:22])[CH3:21].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: O
Solvent: OCCOCCO
Product: CC(C)CN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A suspension of 5.2 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 4.5 g of 1-isobutyl-2-aminomethylpyrrolidine in 20 ml of diethylene glycol is heated at 130°-140° C. and stirred for 18-19 hours. The reaction solution is cooled to room temperature and poured into 150-200 ml of water while stirring. Under ice-cooling crystals are deposited thoroughly and collected by suction filtration. The crude crystals are washed with cold water, dissolved in chloroform and separated on a column of silica gel (developing solvent: methanol/chloroform=1/9). Crystals obtained are recrystallized from about 35 ml of methanol to give crystals of N-(1-isobutyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1F.[CH3:10][S-:11].[Na+]>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:11][CH3:10]
Reactant: C[S-]
Reactant: Cc1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1ccc(C)cc1Br
Temperature: 125 °C
Reaction time: 8 h

Procedure:
The 2-bromo-1-fluoro-4-methylbenzene (2.00 g, 11.0 mmol) was dissolved in dimethylacetamide (5.3 mL) followed by the addition of sodium thiomethoxide (0.82 g, 12.0 mmol). The reaction was heated at 125° C. for 5.5 h. The reaction was then cooled to rt and stirred overnight. The reaction was then diluted with water (200 mL) and the mixture was extracted with EtOAc (3×125 mL). The combined organic layers were washed with water (1×150 mL) and brine (1×100 mL) and dried over MgSO4. The crude product was purified by column chromatography (silica gel, 0 to 40% EtOAc:hexanes) to give (2-bromo-4-methylphenyl)-(methyl)sulfane. 1H NMR (400 MHz, chloroform-d) δ ppm 7.38 (1H, d, J=0.8 Hz), 7.09-7.13 (1H, m), 7.06 (1H, d), 2.47 (3H, s), 2.31 (3H, s).
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1>O1CCCC1>[F:25][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[C:21]([F:22])([F:23])[F:24])[CH2:14][N:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[NH2:12]
Reactant: NNc1ccc(F)cc1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(C(F)(F)F)c(F)c1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 3.17 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (598 mg, 2.33 mmol; Alfa Aesar) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 250 (M+H−NH3)+.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:43]([O:54][CH2:55][CH3:56])(=[O:53])[CH:44]([CH:46]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[OH:47])[OH:45]>CCOCC>[F:31][C:30]([F:32])([F:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:45][CH:44]([CH:46]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[OH:47])[C:43]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(O)C(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino)benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartarate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CC([O-])(C)C.[K+].CS(O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])(=O)=O.O>C1COCC1>[F:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:10]1[CH:11]=[CH:12][N:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]1=[O:14]
Reactant: CN1CCN(c2ncc[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-methyl-1-piperazinyl)-2(1H)-pyrazinone (obtained in Step 2 above; 0.5 g, 2.6 mmol) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temp, HPLC showed only 50% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried (Na2SO4) and concentrated to yield 1.08 g of the crude product as a yellow oil. Purification by chromatography on silica gel [eluent: 2% MeOH in CHCl3+NH3 (g)] gave the title compound as a yellow oil, which solidified upon cooling. Yield: 304 mg (32%). HPLC purity: 100%. MS m/z 369 (M+H)+. HRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1462.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.62 mmol), morpholine (43 mg, 0.49 mmol) and DIPEA (0.22 mL, 1.2 mmol) in DMF (2 mL). MS (LC-MS): 317.0 [M−55]+; tR (HPLC conditions c): 4.65 min.
Reaction SMILES: C([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([NH:24][CH2:25][CH2:26][NH:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:48]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([N:24]1[CH2:25][CH2:26][N:27]=[C:28]1[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C2=NCCN2C(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 85 °C
Yield: 50 %

Procedure:
A mixture of N-{2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-4-methyl-benzamide (2.8 g, 5.5 mmol) and phosphorus oxychloride (9.4 mL, 100 mmol) in toluene (60 mL) was heated at 85° C. for 7 hours, then heated at reflux for 1 hour. The reaction was concentrated and the residual phosphorus oxychloride removed by toluene azeotrope. The residue was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated. The resultant residue was purified by flash chromatography (0→8% methanol/methylene chloride) to give 1.4 g (50%) of the title compound. MS(ES+) m/e 485 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([Cl:21])=[CH:4][C:3]=1[Cl:22].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:22][C:3]1[C:2]([NH2:1])=[N:7][C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[C:5]([Cl:21])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CCNCC2)c(Cl)cc1Cl
Yield: 100 %

Procedure:
tert-butyl 4-(6-amino-3,5-dichloropyridin-2-yl)piperazine-1-carboxylate (110 mg, 0.305 mmol,) was treated with 50% TFA/DCM for 1 h, then drained and dried in vacuum to give 3,5-dichloro-6-(piperazin-1-yl)pyridin-2-amine (110 mg, 0.305 mmol). 1H-NMR (CD3OD-d4, 500 MHz): δ7.51 (1H, s), 3.51 (4H, m), 3.31 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([C:12]([OH:14])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([C:12]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=3)=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(Cl)ccc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
7-Chloro-4-hydroxy-3-quinolinecarboxylic acid (500 mg) (Org. Syn. Coll. 3:272-275 (1955)) is dissolved in N,N-dimethylformamide (20 mL) and to the mixture is added 1,1'-carbonyl diimidazole (399 mg). The mixture is heated at 50° C. for 20 h and then allowed to cool to rt. The mixture is treated with water (200 mL) and then after 5 min, 4-chlorobenzylamine (300 mL) is added. The mixture is allowed to stir at rt for 2 days and then is poured into water (50 mL) and the resulting white precipitate is filtered. The crude product is recrystallized (acetic acid, water) to afford 481 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of tert-butyl(trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropylcarbamate (11 g, 26.37 mmol) in dioxane (110 mL) at 0° C., HCl in Dioxane (110 mL) was added and stirred for 1 h. After completion, the solvent was evaporated and residue was triturated with Et2O (15 mL) to give crude salt. The crude salt was dissolved in water (150 mL), basified with Na2CO3 solution, extracted with EtOAc (3×100 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (8.2 g, 98%) (trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropanamine
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>O>[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([OH:10])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(O)cc(=O)[nH]1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCc1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
20 g (0.145 mol) of 6-ethyl-4-hydroxy-1-H-2pyridone are suspended in 60 ml of 65% strength HNO3 and heated to 65° C. The strongly exothermic reaction is kept under control by cooling with ice. After the reaction subsides, 120 ml of water are added and the mixture is cooled with ice. After 30 minutes, the precipitate is filtered off with suction and dried.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)O1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:9]3[CH:10]=[CH:11][C:12]([O:13][C:14]4[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=4)=[CH:22][CH:23]=3)[C:34]=12
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)cc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.63 g, 0.00819 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.01 g, 0.00683 mol), tetrakis-(triphenylphosphine)palladium (0.473 g, 0.00041 mol) and sodium carbonate monohydrate (2.12 g, 0.0171 mol) was heated in a mixture of ethylene glycol dimethyl ether (80 mL) and water (40 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (100 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (2.45 g, 0.00483 mol) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][CH2:33][O-:34].[Na+]>C(O)C>[CH2:33]([O:34][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:32]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
The mixture of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (23 mg, 0.050 mmol), NaOEt (10 mg) in ethanol (1 mL) was refluxed at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15.0 mg, 64%).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[N:14]=[CH:13][CH:12]=[CH:11]2)(C)(C)C>[OH-].[Na+]>[CH3:18][C:17]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:7][C:6]([OH:19])=[O:5]
Reactant: Cc1cc2ncccc2cc1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2ncccc2cc1CC(=O)O

Procedure:
3.2 g of (7-methyl-quinolin-6-yl)-acetic acid tert-butyl ester in 25 ml of aqueous NaOH (4N) was heated to reflux for 4 h. The mixture was washed with ethyl acetate and added concentrated hydrochloric acid to pH 7. A white solid formed which was filtered and dried to return the title compound (1.5 g, 71.1%). 1H NMR (DMSO-d6, 300 MHz) δ 12.46 (s, 1H), 8.82 (m, 1H), 8.26 (m, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.44 (m, 1H), 3.80 (s, 2H), 2.44 (s, 3H) ES-MS m/z: 202 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:29][CH3:28])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 101.3 %

Procedure:
In a mixture of 2.3 g of 40% methylamine aqueous solution and 10 mL of tetrahydrofuran, a solution of 1.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 10 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was continued to stir further for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed with 50 mL of water, then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:10]([OH:12])=O)=[CH:7][O:8][CH:9]=1)=[O:4].[F:13][C:14]([F:24])([F:23])[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:23][C:14]([F:13])([F:24])[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:10]([C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][O:8][CH:7]=2)=[O:12])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(SC(F)(F)F)c1
Reactant: COC(=O)c1cocc1C(=O)O
Product: COC(=O)c1cocc1C(=O)Nc1cccc(SC(F)(F)F)c1
Yield: 78 %

Procedure:
Methyl 4-(3-(trifluoromethylthio)phenylcarbamoyl)furan-3-carboxylate is prepared from 4-(methoxycarbonyl)furan-3-carboxylic acid and 3-(trifluoromethylthio) aniline following Method G (yield=78%). 1H NMR (300 MHz, CHCl3) δ 11.66 (s, 1H), 8.29 (s, 1H), 8.22-8.09 (m, 1H), 7.96-7.82 (m, 2H), 7.50-7.37 (m, 2H), 3.99 (s, 3H); ESI(−) calcd. for C14H9F3NO4S (344.02). Found 344.0