Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[Na+].[Na+].C(OC(=O)[N:22]([C:39]1[CH:44]=[C:43](Cl)[N:42]=[C:41]([CH3:46])[N:40]=1)[C:23]1[S:24][C:25]([C:28](=[O:38])[NH:29][C:30]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[CH:26][N:27]=1)(C)(C)C.C(NC(C)(C)C)(C)(C)C.C(O)C(N)(CO)CO>O.CS(C)=O>[CH3:36][C:35]1[C:30]([NH:29][C:28]([C:25]2[S:24][C:23]([NH:22][C:39]3[CH:44]=[C:43]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:42]=[C:41]([CH3:46])[N:40]=3)=[N:27][CH:26]=2)=[O:38])=[C:31]([Cl:37])[CH:32]=[CH:33][CH:34]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Cl)cc(N(C(=O)OC(C)(C)C)c2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Agent: CC(C)(C)NC(C)(C)C
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Reaction time: 5 h
Yield: 80 %

Procedure:
In a reaction flask 283.5 ml dimethylsulfoxide, 29.83 g 1-(2-hydroxyethyl)piperazine (0.229 mol), 12.08 g sodium carbonate (0.144 mol), 56.70 g ter-butyl-6-chloro-2-methylpyrimidin-4-yl-(5-(2-chloro-6-methylphenylcarbamoyl)thiazol-2-yl)carbamate (0.114 mol) were charged at a temperature of about 25° C. and the reaction mixture was kept under these conditions for about five hours. At the end of the reaction, 760 ml water were added, the mixture was kept under stirring for about 30 minutes and the formed solid was filtered, washed with water (4×260 ml) and suspended in 440 ml methanol. 42.88 g di-terbutylamine (DBTA, 0.120 mol) were added, the temperature was brought to the solvent reflux value and 15.19 g tromethamol (TRIZMA) (0.125 mol) were added. The temperature was brought to about 25° C. and the formed solid was filtered, washed with methanol (2×45 ml) and dried in oven under vacuum at a temperature of about 50° C. for eight hours to give 44.51 g dasatinib.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][C:4]([C:11]([OH:13])=[O:12])=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C([O:43][C:44](=[O:63])[C@H:45]([CH3:62])[CH2:46][C@H:47]([NH2:61])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OC([C@H](C)C[C@H](NC(C1OC(C(O)=O)=CC(=O)C=1)=O)CC1C=CC(C2C=CC=CC=2)=CC=1)=O)C1C=CC=CC=1.B(Cl)(Cl)Cl.Cl>CN(C=O)C.C(Cl)Cl.O>[C:52]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:51]=[CH:50][C:49]([CH2:48][C@@H:47]([NH:61][C:8]([C:6]2[O:5][C:4]([C:11]([OH:13])=[O:12])=[CH:3][C:2](=[O:1])[CH:7]=2)=[O:10])[CH2:46][C@H:45]([C:44]([OH:63])=[O:43])[CH3:62])=[CH:54][CH:53]=1
Reactant: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C(O)c1cc(=O)cc(C(=O)O)o1
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)cc(C(=O)O)o1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)cc(C(=O)O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-oxo-4H-pyran-2,6-dicarboxylic acid (99 mg. 0.535 mmol) in DMF (10 mL) is added HOBt (98 mg. 0.643 mmol) and EDCI (123 mg, 0.643 mmol) and the mixture is stirred at room temperature for 10 minutes. To this is then added (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (200 mg, 0.535 mmol) and triethylamine (0.224 mL, 1.61 mmol) and the mixture is stirred at room temperature for 48 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to elute the product, 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 540.2 (M+1). Next, to a solution of 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid (100 mg, 0.185 mmol) in methylene chloride (5 mL) is added BCl3 (65.1 mg, 0.556 mmol) and the mixture is stirred at room temperature for 10 minutes. The mixture is acidified to pH 2-3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to elute the product. The proper fractions are lyophilized to furnish 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 450.1 (M+1); 1H-NMR (400Hz, DMSO-d6); δ ppm 1.07 (d, J=7.07Hz, 3H), 1.59 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.84 (d, J=6.69Hz, 2H), 4.19 (m, 1H), 6.84 (s, 1H), 6.93 (s, 1H), 7.32 (dd, J=8.08Hz, 6.57Hz, 3H), 7.45 (t, J=7.83Hz, 2H), 7.58 (d, J=8.21Hz, 2H), 7.64 (d, J=7.33Hz, 2H), 8.61 (d, J=8.72Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:25]=[O:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[NH:43][C:42]3[CH2:41][CH2:40][NH:39][C:38](=[O:44])[C:37]=3[CH:36]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CO.C(Cl)Cl>O1CCOCC1.O.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]>[C:1]([NH:5][C:6]1[C:7]([CH:25]=[O:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:35]1[NH:43][C:42]3[CH2:41][CH2:40][NH:39][C:38](=[O:44])[C:37]=3[CH:36]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: CC(C)(C)Nc1nc2c(B3OC(C)(C)C(C)(C)O3)cccc2nc1C=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C=O
Temperature: 105 °C
Yield: 18.6 %

Procedure:
A mixture of 3-(tert-butylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-2-carbaldehyde (307a) (600.0 mg, 1.18 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (407 mg, 1.89 mmol), K2PO4 (753 mg, 3.55 mmol), X-Phos (Strem Chemicals, Inc., 56.4 mg, 0.12 mmol), and Pd2dba3 (Aldrich, 54.1 mg, 0.06 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2.0 mL) was heated under argon at 105° C. for 1 h. The reaction mixture was cooled to RT, diluted with water (30 mL), and extracted with 5% MeOH/DCM (3×30 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde (79.0 mg, 0.22 mmol, 18% yield) as a dark-red solid: m/z (ESI, +ve) 364.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[C:5]([C:23]([F:24])([F:26])[F:25])[CH:4]=1
Reactant: COC(=O)c1ccc(CC(=O)Nc2ccc(OC)cc2C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(NC(=O)Cc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Temperature: 50 °C
Yield: 89 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of methyl 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoate INT-54 (113 mg, 0.31 mmol) in EtOH (10 mL) was added 1 N NaOH (1 mL). The reaction mixture was heated to 50° C. for 3 h, concentrated, diluted with water, acidified with 1 N HCl and extracted with EA and DCM. The organic layers were combined, dried over Na2SO4 and concentrated to provide 97 mg (89%) of 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoic acid INT-55. LCMS-ESI (m/z) calculated for C17H14F3NO4: 353; found 354 [M+H]+, tR=2.84 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.13 (s, 1H), 7.05 (m, 2H), 3.82 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[NH2:7][C:8](N)=[O:9]>O>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][C:8]([NH2:7])=[O:9]
Reactant: CC(C)(N)CN
Reactant: NC(N)=O
Solvent: O
Product: CC(C)(N)CNC(N)=O

Procedure:
Alternatively, the urea of this example was prepared as follows: A mixture of 26.5 g (0.3 mol) of 1,2-diamino-2-methylpropane, and 18 g (0.3 mol) of urea in 150 ml of water was refluxed for 4 hours. The mixture was evaporated in vacuo. The residue was dissolved in chloroform, filtered and evaporated to form a solid which was recrystallized in ethyl acetate to give 15 g of product (38%), m.p. 87°-90° C. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22][CH3:23])=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:23])=[O:32])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SC)nn2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(C)=O)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole (150 mg, 0.458 mmol) and m-chloroperbenzoic acid (119 mg, 0.687 mmol) in dichloromethane (1.5 mL) was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-2% methanol in dichloromethane) to give 1,5-bis(4-methoxyphenyl)-3-(methylsulfinyl)-1H-1,2,4-triazole (152 mg, 96.6% yield).