Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5].[CH2:34]([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH2:36].C(#N)C>C1(C)C=CC=CC=1>[CH:34]([C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5])=[CH:35][CH3:36]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)cc2)c2ccc3ccccc3c2N1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC=Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
5-[4-(2-Iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (70 mg, 0.128 mmol), allyltributyltin (98 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium(0) (15 mg, 12.8 μmol) were dissolved in anhydrous toluene (0.6 mL), and the solution was stirred at 110° C. for 16 hours. The reaction mixture was left to cool, and then added with acetonitrile, the mixture was washed with petroleum ether, and the solvent of the acetonitrile layer was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (40 mg, yield 68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25]>>[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 46.9 %

Procedure:
3-[3-(4-Methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (87 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1, step 5 above. No solid precipitated out. The reaction solution was rotary evaporated and purified by flash chromatography and eluting with (dichloromethane: methanol 13/1, 10/1, 8/1) to give (70 mg, 47% yield) of 3-[1-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.Br[CH2:24][C:25]#[N:26].Cl>O1CCCC1.C(OCC)(=O)C>[C:25]([CH2:24][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20])#[N:26]
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CC#N)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To lithium bis(trimethylsilyl)amide (1.0 Min tetrahydrofuran) (18.73 mL, 18.73 mmol) at −78° C. was added methyl 2-(4-fluorophenyl)acetate (3.00 g, 17.84 mmol) as a solution in tetrahydrofuran (5 mL) dropwise. During the addition, a white solid precipitated. After the addition, the reaction was placed in an ice bath and stirred for 1 hour. 2-Bromoacetonitrile (2.354 g, 19.62 mmol) was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to stir for an additional 1 hour. The reaction was poured into a mixture of 1 N HCl (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrate. The resulting reside was chromatographed over silica gel (SF40-115, Analogix®) eluting with a gradient of 5% to 50% ethyl acetate/hexanes (Flow=85 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 2H), 7.13-7.01 (m, 2H), 3.93 (t, J=7.6, 1H), 3.73 (s, 3H), 3.02 (dd, J=7.2, 16.8, 1H), 2.81 (dd, J=8.0, 16.9, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.O.[CH3:40]COC(C)=O>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[N:15]\[NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:40])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)/[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(N/N=C3\C(=O)N(c4ccc(C)c(C)c4)N=C3C)c2O)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Pure 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (Eltrombopag) (20 g, 0.045 mol) was suspended in a mixture of MeOH/THF=1/1 (400 mL). The suspension was heated to reflux and sulfuric acid (5 mL) was added drop wise. The reaction mixture was refluxed overnight, cooled to room temperature and evaporated to obtain an oily residue. Water (200 ml) was added to the and a thick suspension was formed. EtOAc (200 ml) was added to form a 2-phase system and the layers were separated. The organic layer was left for half an hour at room temperature resulting in formation of orange crystals. The crystals were filtered, washed with 2×20 mL EtOAc and dried in a vacuum oven at 35° C./0 bar for 2 hours, giving 17.17 g of (Z)-methyl 3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carboxylate (Yield: 83.3%); (HPLC: >95%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24](O)=[O:25])[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:63])[C@H:58]1[CH2:62][CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:60]3[CH2:61][CH2:62][C@H:58]([N:57]([CH3:63])[CH3:56])[CH2:59]3)=[O:25])[C:13]2=[O:27])[CH:7]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](N(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50 mg, 0.11 mmol), HATU (46.6 mg, 0.12 mmol), and dimethyl-(S)-pyrrolidin-3-yl-amine (14.0 mg, 0.12 mmol) DCM (2 ml) is added. The mixture is treated with DIPEA (48.6 μL, 2.79 mmol) and stirred at RT for 1 hour. DCM (5 ml) is added to the mixture and washed with 1M HCl. The acidic aqueous phase is treated with 1M NaOH until the pH is adjusted to pH of 7-8. The product is extracted from the aqueous phase with EtOAc (3×10 ml). The organic portions are combined, washed with water (10 ml), dried (MgSO4), filtered and concentrated to afford the title compound, [M+H]+ 544
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:31][CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:31][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[O:10])[S:5][C:6]=1[Br:7]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cc(Br)c(Br)s1
Yield: 71.8 %

Procedure:
To a solution of 2.55 g (8.91 mmol) of 4,5-dibromothiophene-2-carboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled-off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 2.79 g of the desired compound (yield: 71.8%, colorless powder).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl.Cl.Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]1([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][OH:1])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: OCc1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1SCCCN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
A mixture of 1.56 g of 2-(hydroxymethyl)thiophenol, 3.77 g of 1-(3-chloropropyl)-4-phenylpiperazine dihydrochloride, 5.02 g of potassium carbonate and 40 ml of dimethylformamide is stirred at 50° C. for 6 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is digested with n-hexane and collected by filtration. 3.42 g of 2-[3-(4-phenylpiperazin-1-yl)propylthio]benzylalcohol are obtained. Yield: 91%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12].[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])[CH2:31][CH2:32]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12]
Reactant: Cc1cc(N2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCN(S(=O)(=O)c3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N5-(1H-Benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-imidazole-4,5-dicarboxamide (1 equivalent), dichloromethane, benzenesulfonyl chloride (1.5 equiv), and DIEA (1.5 equiv.) were added and stirred at room temperature. After 1 hour, LC-MS indicated the reaction was complete. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified by reverse phase HPLC (aqueous ammonium acetate/acetonitrile to give N5-1H-benzimidazol-2-yl-N4-{2-methyl-4-[4-(phenylsulfonyl)piperazin-1-yl]phenyl}-1H-imidazole-4,5-dicarboxamide in 43% yield. 1H-NMR (400 MHz, DMSO-d6): δ 10.9 (s, br, 1H), 8.36 (s, 1H), 7.80 (m, 2H), 7.73-7.64 (m, 4), 7.43 (m, 2H), 7.33 (m, br, 1H), 6.97 (m, br, 2H), 3.31 (s, br, 4H), 3.09 (s, br, 4H). 2.24 (s, 3H). MS (EI): 585 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][OH:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: OCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nc(Nc2cccc(Cl)c2)ncc1COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of {2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (200 mg), phenol (70 μL), triphenyl phosphine (190 mg) and dichloromethane (4 mL) was added diethyl azodicarboxylate (330 pt), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained pale yellow solid was washed with ethanol-water to obtain N-(3-chlorophenyl)-5-(phenoxymethyl)-4-(trifluoromethyl)pyrimidin-2-amine (55 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH2:19][OH:20].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[CH:19]=[O:20]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2CO)c(C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C=O)c(C)c1

Procedure:
The title compound was prepared by oxidation of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-methanol with pyridinium chlorochromate in methylene chloride at room temperature. The desired product was isolated after column chromatography to give a green solid (80% yield). 1H NMR(CDCl3) d 10.66(s,1H), 6.91(s,3H), 2.31(s,3H), 2.07(s,3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH3:3].[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])#[N:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:12][CH:11]=1)=[O:19])#[N:14]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN(C)Cc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(CNC(=O)c2cccc(C#N)c2)cc1

Procedure:
Prepared analogously to Example 9d from 4-dimethylaminomethyl-benzylamine, 3-cyanobenzoylchloride and triethylamine in methylene chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:19]3=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:39])[CH2:9]1)=O)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=3)[N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:15]2=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCN(C(=O)OC(C)(C)C)C3)C2=O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCNC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
3-[3-(4-Methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmols) (from Example 4a supra) was dissolved at 0° C. in a 50% trifluoroacetic acid in dichloromethane solution (5 mL) that contained water (300 μL). After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by adding solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated to the crude product. This material was dissolved in tetrahydrofuran and precipitated with an excess of pentane to give 3-(4-methoxy-phenyl)-7-phenylamino-1-piperidin-3-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 47 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[NH3:38].CO>>[NH2:38][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])(=[O:29])=[O:28])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (156 mg, 0.267 mmol) and ammonia in methanol (10 mL, 70 mmol), the title compound was obtained as a yellow solid (53 mg, 33% yield). MS (ESI): 564 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[NH:21][N:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>C1COCC1.CN1C(=O)N(C)CC1.[Pd]>[Cl:35][C:31]1[CH:30]=[C:29]([NH:28][C:26]2[N:25]=[CH:24][N:23]=[C:22]3[NH:21][N:20]=[C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[C:27]=23)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CN1CCN(C)C1=O
Product: CC(C)[C@H](N)C(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
In 4 ml of THF/DMEU 1:3, 40 mg (0.08 mmol) of rac.-3-([N-benzyloxycarbonylvalyl]-amino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Example 8) are hydrogenated in the presence of 10 mg of Pd/C (10%) and 10 μl of 1,2-dichlorobenzene. The catalyst is filtered off, and the filtrate is partially concentrated by evaporation in a rotary evaporator, poured into 30 ml of water and again filtered and the filtrate is concentrated by evaporation under a high vacuum first at RT and finally at 50° C. to yield rac.-4-(3-chlorophenylamino)-3-(valyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=9.2; FAB-MS: (M+H)+=360.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:30])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OC(C)(C)C)=[O:24])[N:9]=[CH:8][N:7]=1.Br[CH2:36][CH3:37].[C:38](=O)([O-])[O-:39].[K+].[K+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH2:36][CH3:37])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:24])[CH2:38][OH:39])[N:9]=[CH:8][N:7]=1
Reactant: CCBr
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
The crude tert-butyl (2R)-2-[({4-[3-chloro-4-fluoroanilino]-7-hydroxy-quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (120 mg) was dissolved in DMA (1 ml), and bromoethane (27 μl) and potassium carbonate (68 mg) were each added in one portion. The reaction mixture was heated at 40° C. for 16 hours and then cooled to room temperature. Trifluoroacetic acid (0.5 ml) was then added and the reaction mixture was stirred for 4 hours at room temperature. Further trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured onto saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was dried (MgSO4) and then concentrated in vacuo to leave a green oil. Purification by flash chromatography, using 2-5% methanol in DCM as eluent, gave the N-(3-chloro-4-fluorophenyl)-7-ethoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine as a pale green solid (83 mg, 52% over three steps); NMR Spectrum (DMSO-d6) 10.2 (s, 1H), 9.50 (s, 1H), 8.30-8.20 (m, 1H), 7.90-7.80 (m, 1H), 7.50-7.40 (m, 1H), 6.80-6.70 (m, 1H), 4.50-4.40 (m, 1H), 4.30-4.20 (m, 1H), 4.30-4.10 (m, 3H), 3.90-3.80 (m, 1H), 3.15-3.05 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.70-1.60 (m, 1H), 1.40 (t, 3H); Mass spectrum MH+ 417.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Br.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:29]=[C:27]([NH:26][C:16]2[CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)=[C:14]([O:13][CH3:12])[CH:15]=2)[S:28][CH:5]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1ccccc1F
Product: COc1cc(Nc2nc(-c3ccccc3F)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 106 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 72 mg (0.33 mmol) 2-fluorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with methylene chloride at room temperature yielding 121 mg (99%) [4-(2-fluoro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light green solid. MS ISP (m/e): 381.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.77 (s, 1H), 9.29 (s, 1H), 8.12 (t, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.38-7.29 (m, 5H), 3.92 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[CH:5]=[O:6].C([BH3-])#N.[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1
Reactant: O=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Yield: 100.5 %

Procedure:
A solution of 3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-benzaldehyde (0.065 g, 0.19 mmol) in DCM (0.5 mL), MeOH (0.5 mL) and acetic acid (0.5 mL) was treated with sodium cyanoborohydride (0.013 g, 0.21 mmol) and the resultant mixture was stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as an off-white solid (0.066 g, quant. yield). 1H NMR (300 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.49 (s, 2H), 4.79 (s, 2H).