Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([Si](C)(C)[O:5][CH2:6][CH2:7][C:8]([C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]3[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=3)[CH:26]=2)=[CH:23][N:24]=1)([OH:19])[CH2:9][CH2:10][O:11][Si](C)(C)C(C)(C)C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[CH:34][N:33]=[C:32]([NH:31][C:27]2[CH:26]=[C:25]([C:22]3[S:21][C:20]([C:8]([OH:19])([CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][OH:5])=[N:24][CH:23]=3)[CH:30]=[CH:29][CH:28]=2)[N:37]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCO[Si](C)(C)C(C)(C)C)c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC(O)(CCO)c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of the product of Step 2 (196 mg, 0.293 mmol) in THF (3 mL) was added TBAF (1 M in THF, 1.465 mL, 1.465 mmol) and the solution was stirred overnight at room temperature. Solvent was removed by evaporation and the residue was purified by flash chromatography to give 3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]pentane-1,3,5-triol (79.8 mg, 0.181 mmol, 61.8% yield) as an off-white fluffy solid. APCI: [M+H]+ m/z 441.1. 1H NMR (500 MHz, acetone-d6): δ 9.30 (1H, s), 8.86 (1H, d, J=4.89 Hz), 8.34-8.32 (1H, m), 8.06 (1H, s), 7.84-7.79 (1H, m), 7.47-7.41 (1H, m), 7.39 (1H, dt, J=7.76, 1.40 Hz), 7.27 (1H, d, J=4.88 Hz), 6.00 (1H, s), 4.04 (2H, t, J=4.74 Hz), 3.77-3.68 (4H, m), 2.25-2.19 (4H, m). rhSYK activity=++
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[CH:21]=[N:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:21]=[N:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=2)[CH:25]=1)[CH3:2]
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1cn2cc(Br)cnc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1ccccc1-c1cnc2nc(C(F)(F)F)cn2c1
Yield: 37.4 %

Procedure:
A mixture of 0.52 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.44 g of 6-bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylphenyl, 1.0 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred under heat-reflux for 4 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.20 g of 6-(2-ethylsulfanylphenyl)-2-trifluoromethylimidazo[1,2-a]pyrimidine (Compound of Present Invention 35).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[O:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[O:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2noc(-c3ccc(C#N)cc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2nc(C(=O)NCCC3CCNCC3)no2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[{2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl}carbamoyl]-5-(4-cyanophenyl)-1,2,4-oxadiazole (2.5 g) in dioxane (30 ml) was added 4N hydrochloric acid in dioxane (13 ml) under ice cooling. After stirring for 5 hours at ambient temperature, the mixture was evaporated in vacuo. The residue was recrystallized from ethanol-ether to afford 3-[{2-(piperidin-4-yl)ethyl}carbamoyl]-5-(4-cyanophenyl)-1,2,4-oxadiazole hydrochloride (1.71 g).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:15]#N.[Na+].CC(O)=O>C(#N)C>[CH3:15][N:7]([CH2:8][C:9]([OH:11])=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of N-phenylglycine (5 g, 33 mmol) and formaldehyde (37% aqueous solution, 20 mL) in acetonitrile (100 mL) was added NaBH3CN (6.8 g) and AcOH (2 mL) and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo, the residue was acidified to pH=3-4 and extracted with CHCl3 several times. The combined organic extracts were dried and concentrated to afford a crude product (5.73 g), which was purified by chromatography on silica gel (EtOAc) to afford the title compound (3.96 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[CH:5]2.[OH-].[K+].[I:14]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[I:14]
Reactant: II
Reactant: Clc1cc2cn[nH]c2cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
To a solution of 5,6-dichloro-1H-indazole (0.50 g, 2.67 mmol) in DMF (8 ml) at room temperature was added powdered potassium hydroxide (450 mg, 8.02 mmol) and iodine (1.02 g, 4.01 mmol). The maroon reaction mixture was stirred at room temperature for 45 min then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated to afford 827 mg (99%) of 5,6-dichloro-3-iodo-1H-indazole as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.79 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C:21](=[O:35])[N:20]2[CH3:36])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8])C.[OH-].[Na+]>CCO>[CH3:37][C:5]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][N:22]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)[C:21](=[O:35])[N:20]2[CH3:36])=[CH:14][CH:15]=1)([CH2:6][CH2:7][CH3:8])[C:4]([OH:38])=[O:3]
Reactant: CCCC(C)(Oc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C)(Oc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)O
Yield: 49.4 %

Procedure:
A mixture of 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid ethyl ester (0.020 g, 0.040 mmol) and 5 N NaOH (0.5 mL) in EtOH (6 mL) was heated at reflux for 1 h. The reaction mixture was cooled and quenched with 1 N HCl. The mixture was then diluted with water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.010 g (53%) 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid. 1H NMR. HRMS (ES+) m/z exact mass calcd for C27H34N2O4F3 [M+1] 507.2471, found 507.2459.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]=[C:25]=S>>[Cl:18][C:3]1[C:2]2[N:1]=[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: COCCCN=C=S
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Product: COCCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Yield: 70.7 %

Procedure:
The method described in Part A of Example 7 was used to treat 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) with 3-methoxypropylisothiocyanate (1.78 g, 13.6 mmol) to provide 2.9 g of 1-{4-chloro-2-[(3-methoxypropyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol after chromatographic purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:21][CH:22](C)[CH2:23][CH2:24][C:25](Cl)=[O:26].O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][Cl:21])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)CCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCCl)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
N-Benzylpiperazine (1.0 g, 5.7 mmole) and triethylamine (1.17 ml, 8.5 mmole) were combined in 20 ml of methylene chloride. 4-Chlorovaleryl chloride (0.945 ml, 8.5 mmole) in 10 ml of methylene chloride was added dropwise over 20 minutes and the reaction mixture stirred for 16 hours at room temperature. Water (20 ml) was then added and the organic layer dried (anhydrous magnesium sulfate) and evaporated in vacuo to a gum. The gum was chromatographed on silica gel with ethyl acetate as eluant and tlc monitoring. Clean product fractions were combined and evaporated to yield the title product as a gum [920 mg, Rf 0.5 (ethyl acetate)].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 67 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.090 g, 0.187 mmol) obtained in step 2 and methanesulfonamide (0.039 mg, 0.412 mmol), the title compound (0.070 g, 67%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].[BH4-].[Na+].Cl>[Pd].CO>[CH3:11][N:9]([CH3:10])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COc1cc(N)ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a two necked 25 mL round bottom flask, charged with 3-(2-methoxy-4-nitrophenoxy)-N,N-dimethylpropan-1-amine (0.5 g, 1.96 mmol) from above, 10 mL of methanol followed by sodium borohydride (0.2 g, 4.2 mmol) and 10% Pd/C (0.05 g). The resulting reaction mixture was stirred at ambient temperature for 1 hour. After this time, the reaction mixture was passed through a cellite cartridge to remove Pd/C. The organic solution was concentrated under vacuo to give a brown solid residue. The resulting solid was treated with hydrochloric acid (2 M in ether). After stirring for 10 minutes, the solid which formed was collected by filtration and washed with water (10 mL) and dried under vacuum to afford the corresponding hydrochloride salt of the title product (0.3 g, 60% yield). 1H NMR (400 MHz, d6-DMSO with D2O) δ: 7.07 (1H, m), 6.99 (1H, m), 6.85 (1H, m), 4.04 (2H, m), 3.79 (3H, s), 3.17 (2H, m), 2.77 (6H, s), 2.13 (2H, m). MS m/z: 225.22 [M+H]+.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)[CH:15]=2)=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)nn1-c1ccccn1
Yield: 89 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 35 of Example C-9 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4cc(S(N)(=O)=O)c(F)cc4F)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (67 mg, 26%). MS (ISN) 507.2 [(M−H)−]; mp 270° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C:36]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:37]=1[C:38]([NH2:40])=[O:39]>CC(N(C)C)=O.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:40][C:38](=[O:39])[C:37]4[C:36](=[CH:44][C:43]([O:45][CH3:46])=[CH:42][C:41]=4[O:47][CH3:48])[N:35]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 4-((4-isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 0.97 mmol), NaHSO3 (0.155 g, 1.50 mmol), and p-TsOH (0.019 g, 0.10 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol) in DMA (7 mL). The reaction was stirred at 130° C. overnight. Then, the mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.122 g, 30%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.54-2.71 (m, 1H), 2.27-2.44 (m, 8H), 0.95 (d, J=6.4 Hz, 6H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH-:38])=[O:37])([CH3:34])([CH3:33])[CH3:32].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: CC(C)(C)OC([NH-])=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(CNC(=O)OC(C)(C)C)cc2)nc1
Temperature: 25 °C

Procedure:
A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.1 g, 0.24 mmol), tert-butoxycarbonylamide (0.083 g, 0.71 mmol), triethylsilane (0.11 mL, 0.083 g, 0.71 mmol) and acetonitrile (1 mL) was treated with trifluoroacetic acid (0.035 mL, 0.46 mmol) and stirred for 48 at ambient temperature. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulphate, filtered and concentrated in vacuo, affording 1-{6-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1.[N:19]([C:22]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:23]=1[C:24](OCC)=[O:25])=[C:20]=[S:21]>O1CCCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:1]3[C:24](=[O:25])[C:23]4[C:22](=[CH:32][C:31]([O:33][CH2:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][CH:29]=4)[NH:19][C:20]3=[S:21])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1N=C=S
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=S)[nH]c3cc(OCc4ccccc4)ccc3c2=O)CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred mixture of 6.25 parts of [1-(2-aminoethyl)-4-piperidinyl](4-fluorophenyl)methanone and 135 parts of tetrahydrofuran was added dropwise a solution of 7.5 parts of ethyl 2-isothiocyanato-4-(phenylmethoxy)benzoate in 45 parts of tetrahydrofuran. Upon completion, stirring was continued for 4 hours at room temperature and for 30 minutes at reflux temperature. After cooling, the product was filtered off and crystallized from a mixture of N,N-dimethylformamide and water. The product was filtered off and dried, yielding 3.8 parts (29%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-(phenylmethoxy)-2-thioxo-4(1H)-quinazolinone; 236.0° C. (dec.) (6).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:18][C:5]1[CH:6]=[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:19])[C:11]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc(Br)cc1-c1nc2c(O)cccc2o1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2oc(-c3cc(Br)cnc3N)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
TFA (20 ml) was added to the mixture. The resulting solution was stirred at 25° C. for 2 hours. The TFA was evaporated and the mixture was basified with a solution 7N of ammonia in methanol. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazol-4-ol (1.040 g) as a solid. NMR Spectrum: (DMSOd6) 6.81 (d, 1H), 7.18 (d, 1H), 7.25 (dd, 1H), 7.94 (bs, 2H), 8.28 (d, 1H), 8.30 (d, 1H), 10.47 (bs, 1H); Mass spectrum: M+H+ 306-308 Iodomethane (0.5 ml) was added to a stirred suspension 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazol-4-ol (820 mg) and potassium carbonate (1111 mg) in DMF (5 ml). The resulting suspension was stirred at 25° C. for 3 hours. The DMF was evaporated under reduce pressure. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 5-bromo-3-(4-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (480 mg) as a solid. NMR Spectrum: (CDCl3) 4.08 (s, 3H), 6.84 (d, 1H), 6.93 (bs, 2H), 7.20 (d, 1H), 7.31 (dd, 1H), 8.23 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 319-321
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30](=[O:33])[CH2:31][CH3:32])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:27]3[CH2:28][CH2:29][N:24]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:25][CH2:26]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCC(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 14.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg, 0.18 mmol), 1-piperazinyl-1-propanone (39 mg, 0.22 mmol), catalytic acetic acid and sodium triacetoxyborohydride (47 mg, 0.22 mmol) to afford 12 mg (15%) of the desired product after purification.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:18][C:19]([C:21]1[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])[CH:12]=[CH:11]2)=[O:7])(C)(C)C>Cl.O1CCOCC1>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([C:19]([NH:18][C:13]3[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=4)[N:14]=3)=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid tert-butyl ester (F-1a1, 9.0 g) was dissolved in 50 mL 4N HCl in dioxane and stirred at room temperature overnight. The solution was concentrated to provide compound F-1a2. The compound was used without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C[N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])(O)=O>ClCCl>[Cl:4][C:2]([CH2:1][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])=[O:3]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cn(CC(=O)Cl)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of 1-(carboxymethyl)thymine (9.2 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.