Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F-].[Cs+].B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:57]1[C:62]([F:63])=[CH:61][C:60]([F:64])=[CH:59][C:58]=1[F:65]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:61]1[C:62]([F:63])=[CH:57][C:58]([F:65])=[CH:59][C:60]=1[F:64])[CH:7]=[CH:6]2
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 90 °C
Yield: 69.5 %

Procedure:
Alternatively, combine trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.93 g, 3.60 mmol), cesium fluoride (5.0 g, 33 mmol), bis(neopentyl glycolato)diboron (1.0 g, 4.4 mmol), bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and acetonitrile (50 mL). Heat the mixture to 90° C. for 20 minutes to obtain a dark-colored solution. Add 2-bromo-1,3,5-trifluoro-benzene (5 g, 23.7 mmol) and heat at 90° C. for 2 hours. Add bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and 2-bromo-1,3,5-trifluoro-benzene (5.0 g, 23 mmol) and heat at 90° C. for 4 hours. Cool to room temperature and filter through a pad of celite and evaporate the solvent. Purify the residue over silica gel, eluting the material with methanol in dichloromethane (0 to 5%), to give 1.30 g (67%) of title compound: mass spectrum (ion spray) m/z=520.2 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.FC1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C(O)(=O)C>O1CCCC1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 2 h
Yield: 57.4 %

Procedure:
64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran, and, while the mixed solution was stirred and cooled on ice, a solution obtained by dissolving 258 g of diethyl malonate in 400 ml of tetrahydrofuran was dropped to the mixed solution through 1 hour and 40 minutes so that the reaction temperature was kept below 20° C. Then, while the reaction solution was stirred and cooled on ice, 200 ml of tetrahydrofuran solution dissolving 142 g of 2,3,4-trifluoronitrobenzene was dropped to the reaction solution through 2 hours so that the reaction temperature was kept below 10° C. After reacting at room temperature for 2 hours, 100 ml of acetic acid was added to the reaction solution and tetrahydrofuran was removed by distillation. To the residue, 1 1 of chloroform, 1.5 1 of water and 100 ml of concentrated hydrochloric acid were added, and the solution was separated. The organic layer was separated from the solution, and the solvent was removed by distillation. To the residue, 250 ml of 4 N hydrochloric acid and 200 ml of acetic acid were added, and the solution was heated under reflux for 11 hours. After removing 150 ml of content solution by distillation, 50 ml of acetic acid and 50 ml of water were added to the solution, and the solution was heated under reflux for 31 hours. After the solution was air-cooled, the precipitated crystal was filtered off, washed with diisopropyl ether and was dissolved in 400 ml of methanol. After treating with active carbon, the solvent was removed by distillation. The precipitated crystal was dispersed in diisopropyl ether and was filtered off to obtain 100 g of the subject compound (1) in a 56% yield.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[CH2:86]([CH2:88][NH2:89])[OH:87]>>[OH:87][CH2:86][CH2:88][NH:89][C:40]([C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][NH:9][CH:10]=3)[CH:3]([CH3:5])[CH3:4])[CH:31]=2)[CH:36]=1)=[O:41]
Reactant: NCCO
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NCCO)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.0 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with ethanolamine (0.26 mL) in a similar manner as described in Example 24-(i) to give the titled compound (1.74 g) as a colorless powder.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]2[C:3]([NH2:18])=[N:4][C:5]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[N:6][C:7]=2[N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:22]=[N:21]1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2c(N)nc(-n3cccn3)nc2-n2cccn2)cn1
Yield: 44.9 %

Procedure:
A mixture of 0.1 g (0.33 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine (Example 1), 0.10 g (0.49 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 0.23 (0.72 mmol) of cesium carbonate and 5 mg (6.5 μmol) of [1,1′-Bis(diphenylphosphino) ferrocene]dichloropaladium (II) dichloromethane complex in 3 ml dioxane and 0.5 ml of water were irradiated with microwaves at 140° C. for 30 min. After cooling to room temperature ethyl acetate was added and filtered by celite. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as eluent to give 45.5 mg (45.3%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].Cl.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:13])=[CH:9][C:8]=1[F:16]
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)O)cc1F
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzoic acid (100 mg, 0.43 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (151 mg, 0.43 mmol) [prepared according to Preparation 3], diisopropylethyl amine (0.4 mL, 2.14 mmol) in DCM (5 mL) was added PyBrop (330 mg, 0.71 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (90 mg, 36%) as a white solid: LCMS (ES) m/z=585 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Nc1cccc(Cl)c1
Product: COCC1COc2cc3ncnc(Nc4cccc(Cl)c4)c3cc2O1
Yield: 61.8 %

Procedure:
The titled compound (25 mg, 63%, m.p. 277-282° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (30 mg, 0.113 mmol) and 3-chloroaniline (28 mg, 0.226 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C1COCC1.CC(O)C>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCOCC3)n2)c1
Temperature: 60 °C

Procedure:
To a solution of triazine A1 (300 mg, 1.0 mmol) in a mixture of THF (4 mL) and iPrOH (4 mL) were added morpholine (87 mg, 1.0 mmol) and DIPEA (200 μL, 1.15 mmol). The mixture was heated for 2 hours at 60° C. and the solvent removed under reduced pressure. The residue was treated with MeOH and the solid title compound (B10) collected by filtration, washed with MeOH, and dried in vacuo. Yield: 93.3 mg (27%), colorless amorphous solid. MS (ES) C14H18N6O3S requires: 350. found: 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11](O)[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:11]1[C:10]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=2[S:8][C:7]2[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:12]1
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(O)C2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Reaction time: 3 h

Procedure:
15.7 G. of 10,11-dihydro-3-methoxy-8--methylthio-dibenzo[b,f]thiepin-10-ol, 250 ml. of benzene and 6 g. of finely powdered calcium chloride are saturated with hydrogen chloride gas at 15° C. over a period of 2.5 hours and subsequently stirred for an additional 3 hours. After the addition of 0.8 g. of active carbon, the precipitate is removed by filtration and washed with benzene. The benzene phase is evaporated under reduced pressure, and there is obtained 10-chloro-10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin having a melting point of 120°-123° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[Cl:13].[I-:14].[Na+].N>O1CCOCC1.[Cu](I)I>[Cl:13][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([I:14])=[CH:11]2
Reactant: [I-]
Reactant: Oc1cc(Cl)c2ncc(Br)cc2c1
Agent: I[Cu]I
Agent: N
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(Cl)c2ncc(I)cc2c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of 3-bromo-8-chloro-6-hydroxyquinoline (5.0 g) (preparation described in WO 2004/108663), sodium iodide (5.8 g) and copper iodide (0.37 g) in dioxane (65 ml) is added N,N″-dimethyl-ethane-1,2-diamine (0.34 g) in a sealed tube under argon. The mixture is stirred at 120° C. for 14 h and upon cooling is treated with aqueous ammonia followed by aqueous hydrochloric (to pH 5). Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gives the required product ((M+1)+306) that is used as such in the next step.
Reaction SMILES: C(N(CC)CC)C.[S:8]([CH2:15][C:16]([OH:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:9]1([S:8][C:15]2[C:16](=[O:18])[O:17][CH2:20][C:21]=2[C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(C2=C(Sc3ccccc3)C(=O)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., triethylamine (335 μL) was added to a solution of thiophenoxyacetic acid (161 mg) and 2-bromo-1-(4-(methylsulfonyl)phenyl) ethanone (272 mg, WO 9500501, example 9, Step 1) in 5 mL of acetonitrile and the mixture was stirred at 0° C. for 1h. The reaction mixture was then cooled to −20° C. and DBU (265 μL) was added. The mixture was stirred for 30 min. at −20° C. and was quenched by addition of 1N HCl. The product was extracted with EtOAc, dried over sodium sulfate and partially purified by silica gel chromatography. The impure product was recrystalized from EtOAc/Hexane to afford the title compound as a solid
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A mixture of 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (16.2 mg, 0.050 mmol), 4(trifluoromethylthio)benzyl bromide (20.3 mg, 0.075 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 60° C. for 15 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-{4-(trifluoromethylthio)benzyl}piperidine (Compound No. 1616) (21.9 mg, 85%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545.2 (M++H, C23H26ClF3N4O2S).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[N:2]1.Cl.[NH2:17][OH:18].O>CN(C)C=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:17][OH:18])=[N:2]1
Reactant: NO
Reactant: O=C(C1=NOCCO1)c1ccccc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(C1=NOCCO1)c1ccccc1O
Yield: 60.8 %

Procedure:
At 80° C., 4.14 g (0.02 mol) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone (III-1) in 20 ml of dimethylformamide are stirred with 2.1 g (0.03 mol) of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 4.7 g of crude product consisting of 15% E isomer and 57.5% Z isomer (HPLC) are obtained. The crude product is chromatographed over silica gel using a mixture of diethyl ether and petroleum ether (1:1). 2.7 g (60.8% of theory) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) are obtained (content according to HPLC analysis: 93.4%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ccnc1C=O)OC
Temperature: 110 °C
Yield: 31.6 %

Procedure:
To a solution of the imidazole-2-carboxaldehyde (0.41 g, 4.27 mmol) in DMF (1 mL) was added 1.1 eq. of 2-bromo-1,1-dimethoxyethane (0.79 g, 4.69 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (248 mg, 1.35 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.9 (s, H), 7.85 (s, H), 7.55 (s, H), 5.82 (m, H), 4.75 (d, 2H), 3.45 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.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:13]3[CH:12]=[CH:11][C:10]([CH:7]([C:8]#[N:9])[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:15][CH:14]=3)[C:34]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(C(C#N)c3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(C#N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (0.120 g, 0.000376 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.083 g, 0.000188 mol), tetrakis-(triphenylphosphine)palladium (0.013 g, 0.000011 mol) and sodium carbonate monohydrate (0.058 g, 0.00047 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 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 purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl cyanide (0.025 g, 0.0000494 mol) as an off-white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C([O:19][C:20](=O)[C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C>C(O)C>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:20](=[O:19])[C:21]([OH:28])=[C:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: O=Cc1ccco1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1ccco1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and Furan-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33]1([C@H:39]([CH3:44])[CH2:40][C:41](Cl)=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>N1C=CC=CC=1.ClCCl>[OH-:31].[NH4+:1].[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH2:40][C@H:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:44])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: C[C@H](CC(=O)Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C[C@@H](C)c1ccccc1
Product: [NH4+]
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 2 %
Yield: 112.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.15 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of (3R)-3-phenylbutanoyl chloride (0.420 g, 2.3 mmol) in dichloromethane (3 mL). The reaction mixture stirred for 20 min at −5° C., then the dry ice/acetone bath was removed and was stirred at room temperature under a nitrogen atmosphere. (3R)-3-phenylbutanoyl chloride (0.210 g, 1.15 mmol) was added to the reaction mixture and was stirred for 2 h. Sodium hydroxide (1 N) solution (10 mL) was added and was stirred over night. The organic solvent was removed under reduced pressure, and dichloromethane (20 mL) was added. The layers were partitioned, and the aqueous layer was extracted with dichloromethane (125 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(3R)-3-phenylbutanamide was purified by flash chromatography on silica gel using 15% (methanol with 2% ammonium hydroxide) in dichloromethane (10 min), 20% (methanol with 2% ammonium hydroxide) in dichloromethane (15 min), 50% (methanol with 2% ammonium hydroxide) in dichloromethane (7 min) to give 0.378 g (57%) pure N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(3R)-3-phenylbutanamide. A warmed solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(3R)-3-phenylbutanamide (0.378 g, 0.649 mmol) in ethyl acetate was treated with a warmed solution of maleic acid (0.226 g, 1.95 mmol) in ethyl acetate. The precipitate was filtered under nitrogen and dried on lyophilizer to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(3R)-3-phenylbutanamide trimaleate.