Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[N:8]=[C:9](SC)[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:13][OH:14])[C@H:3]1[OH:15].Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CCO>[N:17]1([C:9]2[O:10][C@H:6]3[CH2:5][C@H:4]([CH2:13][OH:14])[C@@H:3]([OH:15])[C@@H:2]([F:1])[C@H:7]3[N:8]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CSC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC[C@H]1C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@H](F)[C@@H]1O
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a solution of (3 aS,4S,5R,6R,7aS)-4-fluoro-6-(hydroxymethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (50 mg, 0.21 mmol) in EtOH (3 mL) was added azetidine hydrochloride (100 mg, 1.06 mmol). The mixture was heated at reflux for 17 h. After cooling, solid NaHCO3 (100 mg, 1.19 mmol) was added and stirred for 10 min. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5%-10% 2 M NH3 MeOH solution in DCM to give the product (3aS,4S,5R,6R,7aS)-2-(azetidin-1-yl)-4-fluoro-6-(hydroxymethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (31.4 mg, 60%) as a white solid. MS m/z 245.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 4.57-4.61 (m, 1H), 4.58 (ddd, J=52.8 Hz, 3.7 Hz, 1.6 Hz, 1H), 4.02 (t, J=7.6 Hz, 4H), 3.85 (ddd, J=26.1 Hz, 7.1 Hz, 3.8 Hz, 1H), 3.66-3.73 (m, 2H), 3.49 (ddd, J=30.2 Hz, 10.0 Hz, 1.5 Hz, 1H), 2.27-2.38 (m, 3H), 2.01-2.09 (m, 1H), 1.73-1.81 (m, 1H); 13C NMR (100 MHz, MeOD) δ 165.85, 93.17 (d, J=178.6 Hz), 80.71, 70.65 (d, J=19.1 Hz), 64.45 (d, J=17.3 Hz), 63.94, 51.87, 35.47 (d, J=5.8 Hz), 28.39, 17.77.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 116) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 486.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[S:8](=[O:25])[CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1SCC2
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cccc(Cl)c1S(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 0.9 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, prepared in Example 24, in 20 ml of acetic acid is added 0.6 ml of 35% hydrogen peroxide with stirring at room temperature and the mixture is stirred for 18 hours at the same temperature. To the residue is added water, and the precipitated crystals are collected by filtration and repeatedly washed with ethanol to give 0.7 g of 8-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide, melting at 217°-219° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C>CN(C=O)C>[CH3:1][N:2]([CH3:23])[C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH2:28][OH:29])=[CH:12][CH:13]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1
Reactant: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenol (98.7 mg) in DMF (2 ml) was added sodium hydride 60% dispersion in mineral oil (15.3 mg). The mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added (2-bromoethoxy)-tert-butyldimethylsilane (153 mg) in DMF (1 ml) dropwise and the mixture was stirred at ambient temperature overnight. The mixture was poured into ice water, extracted with AcOEt, washed with H2O and saturated aqueous sodium chloride solution. The aqueous layer was reextracted with AcOEt. The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in EtOH (2 ml) . To this solution was added concentrated hydrochloric acid (100 μl) and the mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated invacuo, and the residue was partitioned between AcOEt and saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=60%. The residual crystals were collected and washed with IPE to give 2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethanol (97 mg) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][CH2:29][Cl:30].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:30][CH2:29][CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: ClCCBr
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (120 mg, 0.338 mmol) in DMSO (2.0 mL) was added 2-bromo-1-chloroethane (485 mg, 3.38 mmol) and Cs2CO3 (330 mg, 1.01 mmol), and the reaction was stirred at ambient temperature for 3 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH, 99:1 to 98:2) yielded the title compound (72 mg, 51%): 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.76-7.73 (m, 5H), 7.59-7.47 (m, 3H), 6.92-6.91 (m, 1H), 6.53-6.51 (m, 1H), 4.74-4.71 (m, 2H), 4.00-3.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([Br:22])[C:18]([F:21])([F:19])[F:20]
Reactant: Cc1cc(F)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)c(NN=C(Br)C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
3.7 g of trifluoroacetaldehyde {2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone was dissolved in 50 ml of N,N-dimethylformamide, and 2.0 g of N-bromosuccinimide was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.4 g of N-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}trifluoroacetohydrazonoyl bromide.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[N:6]1[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])=[O:4].[OH-].[Na+]>CO.O>[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=4)[CH2:13][CH:5]3[C:3]([OH:4])=[O:2])[C:17](=[O:26])[NH:18]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C1Cc2ccc(OC)cc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)N(C1(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc31)C(C(=O)O)C2
Yield: 103.4 %

Procedure:
A mixture of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester (250 mg, 0.5 mmol), NaOH (40 mg, 1.0 mmol) in methanol (4 mL) and water (2 mL) was heated to reflux for 3 hr. Then the mixture was concentrated in vacuo to remove methanol. Water (10 mL) was added to the residue. The resulting mixture was acidified with acetic acid, extracted with ethyl acetate. The organic layer was washed with water, dried with Na2SO4, concentrated in vacuo to give 250 mg rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid. MS: [M−H]−=481
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[CH2:16]([CH2:18][NH2:19])[OH:17].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:19]([CH2:18][CH2:16][OH:17])[CH:6]=[CH:5]2
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Reactant: NCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Reaction time: 1 h

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (1.0 g, 0.00443 mol), ethanolamine (0.401 mL, 0.00665 mol), triethylamine (1.24 mL, 0.00886 mol) and methanol (30 mL, 0.7 mol) and the reaction was subjected to microwave at 100° C. for 1 hour. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as a yellow solid. MS m/z=269.4 (M+H). 1H NMR (400 MHz; CDCl3) 8.41 (d, J=8.56 Hz, 1H), 7.52 (d, J=8.56 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.31 (d, J=8.56 Hz, 1H), 4.17 (t, J=44.88 Hz, 2H), 3.99 (t, J=5.11 Hz, 2H), 2.55 (bs, 1H).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[CH:23]=[CH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:35][C@@:29]1([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:12][CH:9]4[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]4)[CH:20]=3)[CH:25]=2)[CH2:33][O:32][C:31](=[O:34])[NH:30]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCCCCC1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
In a 40 mL vial, 4-Pentyl-cyclohexanol (1144.4 mg, 0.0067202 mol) was diluted with tetrahydrofuran (30.0 mL, 0.370 mol, Acros) and subsequently (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (1.4924 g, 0.0061350 mol) and triphenylphosphine (2105.5 mg, 0.0080275 mol) were added and the mixture was stirred. Diethyl Azodicarboxylate in toluene (2.6 mL, 0.0086326 mol, Aldrich) was added, and the mixture was then stirred at room temperature for 38 h. The reaction mixture was evaporated to dryness and chromatographed 0-100% EtOAc/Hexanes (adsorbed onto silica gel). Isolated was 0.6142 g (18%) in approx 70% purity, the remainder being reduced DEAD reagent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12])#[N:2].[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([O:12][CH3:13])=[C:3]([CH:8]=1)[C:1]#[N:2])([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])cc1C#N

Procedure:
A mixture of 2-cyano-4-nitrophenol (3.5 g, 21 mmol), K2CO3 (5.9 g, 42 mmol), and MeI (9.08 g, 64 mmol) in acetone (50 mL) was heated at reflux overnight. The mixture was cooled and concentrated, taken up in H2O, stirred, filtered the yellow solid, dried by air (3.0 g, 79%). 1H NMR (400 MHz, CDCl3): d 4.08 (s, 3H), 7.12 (d, J=9.2 Hz, 1H), 8.5 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:30][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cc1cccc(C=O)n1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 182 mg (1.5 mmol) of 6-methyl-pyridine-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methyleneamino)-1H-pyrazolo-[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in ethyl acetate yield 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p: 231-233° C.; HPLC: tRet(grad20-100)=6.6; MS: (M)+=365.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)O1.[CH2:21]([N:23]1[CH:27]=[C:26](I)[C:25]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:24]1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:21]([N:23]1[CH:27]=[C:26]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)[C:25]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:24]1)[CH3:22]
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CCn1cc(I)c(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2cn(CC)nc2-c2cccs2)ccn1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide (0.60 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.05 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (0.50 mmol) in 3.3 mL degassed dioxane and 1.1 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 15 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 95:5 to 0:100) to afford 152 mg N-{4-[1-ethyl-3-(2-thienyl)-1H-pyrazol-4-yl]pyridin-2-yl}propanamide (93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>[Pd].C(OCC)(=O)C.CO>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[CH:16][C:10]=3[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(-c2nc3cc(N4CCN(CCO)CC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2nc3cc(N4CCN(CCO)CC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-{4-[2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-piperazin-1-yl}-ethanol (1.0 g, 2.6 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (200 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 2-{4-[2-(3,4-diamino-phenyl)-1H-benzoimidazol-5-yl]-piperazin-1-yl}-ethanol as a reddish solid that was used in the next step without any purification.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[S:42]1[C:46]2[CH:47]=[CH:48][C:49]([NH2:51])=[CH:50][C:45]=2[N:44]=[CH:43]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1COCC1>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:51][C:49]3[CH:48]=[CH:47][C:46]4[S:42][CH:43]=[N:44][C:45]=4[CH:50]=3)=[N:3][CH:4]=[C:5]([CH:34]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH3:35])[CH:6]=2)[N:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCOCC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A mixture of 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.300 g, 0.537 mmol) and benzo[d]thiazol-5-amine (0.202 g, 1.343 mmol) in THF (10 mL) was chilled to 0° C. in an ice bath. Then sodium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 2.148 mL, 2.148 mmol) was added into the mixture via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under an inert atmosphere for 1 h. The reaction mixture was diluted with water (30 mL) and the organic layer was extracted with chloroform (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude bis-PMB protected product as a tan oil. This crude material was treated with trifluoroacetic acid (1.8 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was placed into a pre-heated bath (70° C.) and allowed to stir under inert atmosphere for 10 min. The mixture was removed from the heat source and allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (10 mL), and then sodium carbonate (1.5 g) was added to the mixture with stirring. The mixture was filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC (Varian, 5-70% acetonitrile in water with trifluoroacetic acid as additive 0.1% v/v in each solvent) to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-morpholinoethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.015 g, 0.033 mmol, 6.23% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 12.24 (s, 1H) 9.36 (s, 1H) 8.92 (s, 1H) 8.75 (s, 1H) 8.36 (s, 1H) 8.06 (d, J=8.61 Hz, 1H) 7.92 (s, 1H) 7.82 (d, J=8.61 Hz, 2H) 3.57 (s, 4H) 3.29-3.46 (m, 1H) 2.50 (d, J=7.82 Hz, 5H) 2.34 (s, 2H) 1.36 (d, J=6.46 Hz, 3H). m/z (ESI, +ve ion) 449.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:5]2.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:38][C:39](O)([CH3:41])[CH3:40]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:39]([CH3:41])([CH3:40])[CH3:38])=[O:23])=[CH:5]2
Reactant: O=C(O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
5-(6-Bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 4.00 g, 10.4 mmol) was dissolved in DCM (100 mL). The flask was cooled to 0° C. in an ice/water bath before TFAA (14.7 mL, 104 mmol) was slowly added. After stirring at 0° C. for 1 h, tBuOH (29.9 mL) was gradually added and the reaction mixture was allowed to warm to RT overnight. The mixture was diluted with DCM and sat. Sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. Chromatography (5-100% EtOAc/hexanes) afforded tert-butyl 5-(6-bromo-2-phenylquinolin-3-yl)pentanoate (18, 3.71 g; Yield=81%, LCMS (M+H)=440).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:20]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C=NCCCl
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (419 mg, 2.18 mmol) and 2-chloroethyl isocyanate (230 mg, 2.18 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled to room temperature and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient), dried and triturated with ethyl acetate/hexanes (1/9) to afford (1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (258 mg, 40%) as a yellow solid. MS M+H calculated 298.10. Found 298.1