Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][C:13]([NH:15][CH3:16])=[O:14].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:17][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[CH:6][N:7]2[CH3:11]
Reactant: CNC(=O)Cc1cn(C)c2ccc(F)c(O)c12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)Cc1cn(C)c2ccc(F)c(OCc3cccc(Cl)c3)c12
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A mixture of 33-6 (40 mg, 0.17 mmol), 1-(bromomethyl)-3-chlorobenzene (35 mg, 0.17 mmol) and Cesium carbonate (166 mg, 0.51 mmol) in acetonitrile (20 mL) was refluxed for 2 h. After cooled to room temperature, the mixture was filtered and the filtrate was evaporated under vacuum. The resulting residue was purified by Preparative TLC (petroleum ether/ethyl acetate=1:3) to give 33-7 (50 mg, 82%) as a white solid. LRMS: calc 360.1 and found: 361.1 [M+1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:29]2[C:33](=[O:34])[CH2:32][CH2:31][C:30]2=[O:35])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)O)c1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)ON2C(=O)CCC2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of 4.43 g. of 6-[4-[bis(2-hydroxyethyl)-aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. dimethylformamide was cooled in ice and treated dropwise with a solution of 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. dimethylformamide. The solution was allowed to warm to room temperature over 16 hours. The mixture was cooled and the N,N'-dicyclohexylurea filtered off. Addition of 180 ml. of isopropanol to the filtrate precipitated the 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester, which was collected by filtration.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>CN(C)C=O>[Cl:20][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
40.5 g (174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 80 ml of N,N-dimethylformamide and the resulting suspension was heated to 80° C. 31.9 g (19.4 ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85° C. The reaction solution was stirred for 30 minutes and then 400 g of ice-water was added thereto with stirring. The mixture was adjusted to pH 11 by adding sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150 ml of 50% aqueous methanol solution and then dried to obtain 42.3 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(Cl)ccnc1C(O)C1CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1c(Cl)ccnc1C(=O)C1CC1
Yield: 98.2 %

Procedure:
A solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanol (7.01 g, 35.5 mmol) in DCM (80 mL) was treated with MnO2 (30.8 g, 355 mmol) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness, affording the title compound (6.82 g, 98%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)=[CH:11]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:26]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:27][C:19]([C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]([CH2:9][CH2:8][CH2:7][OH:6])[CH:11]=3)=[CH:20][C:21]=12
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21

Procedure:
A solution of 6-{1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazine [29 g, Reference Example 3(a)] in tetrahydrofuran (500 mL) under nitrogen was treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran (144 mL, 1.0M).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OCC)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OCC)cc1
Yield: 23.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-ethoxyphenyl)-3-oxopropionate (84.5 g) and 4-nitrobenzylamine (87.1 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-ethoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (28.1 g), melting point 214-217° C.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6]Cl)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1.[I-].[Na+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1
Reactant: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(C3OCCOC3CCn3cncn3)ccc2N1
Temperature: 80 °C

Procedure:
10.5 Grams (35.5 mM) of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril was dissolved in 10.6 g (71 mM) of dimethylformamide, to this solution was added 10.6 g (71 mM) of sodium iodide, 5.4 g (78.1 mM) of 1H-1,2,4-triazol and 6.5 ml (46.2 mM) of DBU, and the whole mixture was heated at 80° C. for 7 hours with stirring. The reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue was extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=40:1), and recrystallized from ethanol-n-hexane to yield 8.0 g of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl]-3,4-dihydrocarbostyril. Next, to a solution of 1 g (3.0 mM) of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl] -3,4-dihydrocarbostyril with 10 ml of DMF was added 3 ml of 5%-hydrochloric acid and stirred for 2 hours at room temperature. After concentration by removal of the solvent, the residue was extracted with chloroform: methanol=3:1. The extract was washed with water, dried with an anhydrous magnesium sulfate, then concentrated by removal of the solvent. The resulting residue was recrystallized from chloroform-ethanol to yield 6-[4-(1H-1,2,4-triazol-1-yl)butyryl]-3,4-dihydrocarbostyril.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH:8]=[CH:7]2)([O-:3])=[O:2].[H][H]>C(O)C.[C].[Pd]>[N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: [H][H]
Reactant: COCC1(C)C=Cc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: [Pd]
Solvent: CCO
Product: COCC1(C)CCc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
9.4 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chromene was dissolved in 100 ml of ethanol and 1.0 g of a 10% palladium carbon catalyst was added and, after sealing hydrogen, the catalytic hydrogenation reaction was carried out at room temperature under normal pressure for 24 hours. After the completion of the reaction, the reaction solution was filtered and then concentrated under reduced pressure to obtain 9.5 g of the objective oily compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:14][CH2:13][CH:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[N:11]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])C)=[O:28])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][C:10]12[N:11]([C:27]([O:29][CH:30]([CH3:32])[CH3:33])=[O:28])[CH:12]([CH2:13][CH2:14]1)[CH2:15][O:35][CH2:34]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N2C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1C2CCC1(CO)COC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate (410 mg, 0.64 mmol) and TBAF (1 M in THF, 4 mL) in THF (2 mL) was stirred at 50° C. for 16 h. Then the mixture was diluted with ethyl acetate (50 mL) and washed with saturated NH4Cl (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford isopropyl 5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 81j (73 mg, 47%) which was used for next step without further purification. MS: calc'd (MH+) 244, measured (MH+) 244.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4cccc(Cl)c4)CC3)nn12

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-chlorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:23]1[CH:22]=[C:21]([CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[NH:25][C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2cc(Cl)c(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60.0 mg, yield 28%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([C:21]#[N:22])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]([N:13]1[C:14]2=[N:15][C:16]([C:21]#[N:22])=[CH:17][CH:18]=[C:19]2[NH:20][C:29]1=[O:30])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C#N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To a stirred solution of (R)-3-(3-amino-6-cyano-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (600 mg, 1.93 mmol) in THF (20 ml) was added CDI (630 mg, 3.87 mmol) and DBU (0.12 ml, 0.77 mmol). The resulting solution was stirred at room temperature for 18 hours after which time the reaction appeared complete. Added silica gel and concentrated. The remaining solid was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-60% EtOAc/hexanes) to give 120 mg (19%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].[N:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:25]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][N:17]=3)[NH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: c1cnc2[nH]ccc2n1
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (18, 50 mg, 0.42 mmol) in 0.8 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 103 mg, 0.42 mmol) and potassium hydroxide (71 mg, 1.3 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 60% ethyl acetate in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (19, 74 mg, 49%). MS (ESI) [M−H+]−=363.5.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=O)=O)[CH:2]=1.C(O)C.S(O)(O)(=O)=O.[OH:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[NH2:28].C([O-])(=O)C.[Na+]>O>[OH:20][C:21]1[C:22]2[C:23](=[N:27][C:7]([C:3]3[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=3)=[CH:9][N:28]=2)[N:24]=[CH:25][N:26]=1
Reactant: Nc1ncnc(O)c1N
Reactant: Cc1cccc(C(=O)C=O)c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2cnc3c(O)ncnc3n2)c1
Reaction time: 17 h

Procedure:
A solution of 3.6 g. of 3-tolylglyoxal in 15 ml. of ethanol was added to a stirred suspension of 3.26 g. of 6-hydroxy-4,5-diaminopyrimidine sulfate in 30 ml. of hot water containing 6.45 g. of sodium acetate. Stirring was continued for 17 hours at room temperature and the formed precipitate was then filtered, washed twice each with methanol and ether to yield 2.7 (28%) of 4-hydroxy-7-(3-tolyl)pteridine. Recrystallization from DMSO/water produced the pure product; melting point 248-50 degrees C. The test results (100 mg/kg; oral) are shown in Table VI.
Reaction SMILES: [CH:1]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[CH:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:19]3[CH2:20][O:21]3)=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C2CCc3ccccc32)cc1
Product: c1ccc2c(c1)CCC2c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-indan-1-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41](S([O-])(=O)=O)C>>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH2:8][CH3:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Reactant: CCS(=O)(=O)[O-]
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1

Procedure:
7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.Cl.[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][N:39]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2cccc(Cl)c2)CC1)O3
Temperature: 50 °C
Yield: 47.4 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (647 mg, 1.44 mmol), 3-chlorophenyl-piperazine hydrochloride (1.0 g, 4.3 mmol) and diisopropylethylamine (0.75 mL, 4.3 mmol) in anhydrous DMSO (6 mL) were heated at 50° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (5% MeOH/CH2Cl) afforded 280 mg (68%) of the desired product as a beige solid: mp 110–112° C.; MS (ESI) m/z nnn [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH2:18][CH:19]=[O:20])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(CCC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-allylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1[CH:29]=[CH:28]C=CC=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:23][CH:29]1[CH2:28][O:23][CH2:12][CH2:13][O:14]1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(O)(CCCNC(=O)OC(C)(C)C)C(=O)OCC
Reactant: c1ccncc1
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)(OC1COCCO1)C(=O)OCC
Reaction time: 5 h

Procedure:
20 Mg of pTS acid are added to a solution of 1.6 g of ethyl 5-tert-butoxycarbonylamino-2-hydroxy-2-ethoxycarbonyl-pentanoate in 12 ml of 1,4-diox-2-ene. After 5 h. at r.t., 0.3 ml of pyridine are added, the excess reagent is distilled under vacuum and the residue is chromatographed on silica gel, to give 1.75 g of ethyl 5-tert-butoxycarbonylamino-2-(1,4-dioxan-2-yl-oxy)-2-ethoxycarbonyl-pentanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C[Si](C)(C)[C:25]1[S:26][C:27]([Sn](C)(C)C)=[CH:28][N:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[S:26]1[C:27]([C:2]2[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[CH:28][N:29]=[CH:25]1
Reactant: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Reactant: C[Si](C)(C)c1ncc([Sn](C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Yield: 85.8 %

Procedure:
N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide (150 mg, 0.400 mmol), 2-(trimethylsilyl)-5-(trimethylstannanyl)-1,3-thiazole (141 mg, 0.440 mmol) (prepared using literature procedure: Dondoni, A.; Mastellari, A. R.; Medici, A.; Negrini, E.; Pedrini, P. Synthesis 1986, 9, 757-760) and Pd(Ph3P)4 (46.2 mg, 0.040 mmol) were placed in a nitrogen purged microwave vial. Dioxane (2 mL) was added and the resultant solution was purged for 10 minutes with nitrogen gas. The reaction mixture was heated to 90° C. for 15 h. Note: Under the reaction conditions the TMS group is removed. The reaction mixture was concentrated and directly purified by column chromatography to yield 130 mg of N-[3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]acetamide (0.343 mmol, 86%) as a yellow powder.