Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:3]=O.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=1[I:18]>CCO>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]2[C:2]([CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:3][N:17]=[C:13]2[C:12]=1[I:18]
Reactant: O=CC(Br)CC(F)(F)F
Reactant: Nc1nccc(Cl)c1I
Solvent: CCO
Product: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Temperature: 150 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A 2.0-5.0 mL microwave vial was charged with 2-bromo-4,4,4-trifluorobutanal (403 mg, 1.965 mmol) dissolved in EtOH (2500 μl). To that stirring solution was added 4-chloro-3-iodopyridin-2-amine (250 mg, 0.982 mmol). The vial was sealed and heated in the microwave for 1 h at 150° C. After 1 hour, LCMS showed clean and complete consumption of the starting material to a single peak with the desired mass (m/z=260 [M+H]+; Methanol/Water/TFA Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The mixture was transferred into a round bottom flask and the ethanol was removed under reduced pressure. The crude mixture was diluted with EtOAc and sat'd sodium bicarbonate. The contents of the flask were transferred into a separatory funnel where the aqueous was extracted twice with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography: (25 g, equilibrated with hexanes, loaded with DCM, initial waste: mL, fraction size: 9 mL 13×100 mm, and eluted with EtOAc in hexanes 0% [115 mL], 10% [150 mL], 20% [400 mL], 30% [400 mL]). Collected fractions to give 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (261 mg, 73.7% yield) as a sticky yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=7.3 Hz, 1H), 7.70 (s, 1H), 6.98 (d, J=7.3 Hz, 1H), 3.72 (q, J=9.9 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=CN=C1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[N:53]=1>C1(C[C@H](CN(C=O)OCC2C=CC=CC=2)C(N2[C@H](C(O)=O)CCN2C(OCC2C=CC=CC=2)=O)=O)CCCC1.ClCCl>[Cl:58][C:54]1[N:53]=[C:52]([NH:51][C:15]([C@@H:14]2[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[N:10]2[C:8](=[O:9])[C@@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:17])[CH:57]=[CH:56][CH:55]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cccc(Cl)n1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Agent: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc(Cl)n2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (as a mixture of diastereomers enriched in (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid) (300 mg, 0.558 mmol) in dichloromethane (5 ml) was added 1-methylimidazole (133 μl, 1.674 mmol) and cooled to 0° C. Mesyl chloride (56 μL, 0.725 mmol) was added dropwise at 0° C. and stirred for 1 hr at rt. The mixture was then treated with 2-amino-6-chloropyridine (86 mg, 0.67 mmol). The solvent mixture was removed. The residue was diluted with MeOH and purified by reverse-phase HPLC to afford 268 mg (0.413 mmol, 74%) of the title compound. LC/MS: (M+H)+: 648.3.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:16]
Reactant: CCCCCC#N
Reactant: Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.93 g (13.4 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.66 g (19.78 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (8.9 mmol) of hexanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue, which was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:52][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 56.5 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (101 mg, 0.138 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluoro-N-(1-methylethyl)benzamide (45 mg, 0.078 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.50 Hz, 6 H), 2.26 (s, 6 H), 3.10 (t, J=8.24 Hz, 2 H), 3.17 (s, 2 H), 3.77 (s, 3 H), 3.94-4.08 (m, 1 H), 4.17 (t, J=8.29 Hz, 2 H), 6.30 (br. s., 1 H), 6.86-6.99 (m, 2 H), 7.31-7.43 (m, 1 H), 7.50 (s, 1 H), 7.92-8.02 (m, 1 H), 8.51 (d, J=7.60 Hz, 1 H), 8.64 (s, 1 H), 9.31 (s, 1 H), 11.20 (br. s., 1 H). (ESIMS (M+H)+=579)
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH3:8])=[O:7])C.[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].P(Cl)(Cl)(Cl)=O>>[C:10]([C:12]1[C:13]([OH:14])=[N:15][CH:8]=[C:6]([OH:7])[C:5]=1[CH3:4])#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)cnc(O)c1C#N

Procedure:
Amine was generated by the condensation of ethylacetoacetate with cyanoacetamide followed by reaction with phosphorus oxychloride to provide 3-cyano-2,5-dihydroxy-4-methylpyridine. Hydrogenation with palladium dichloride gave the 3-cyano-4-methylpyridine which was hydrogenated with Raney nickel in ammonia and ethanol to afford the desired amine (J. Org. Chem. 1959, 25, 560.).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:25]([F:37])[CH:24]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:18][CH2:19]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[C:25]([F:37])[CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (1.0 g) and rhodium acetate (dimer, 0.044 g) in toluene (10 mL) was added dropwise ethyl diazoacetate (0.83 mL) at 100° C., and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.47 g, 42%).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([O:9][CH:10]([O:12][C@H:13]([CH3:21])[C:14](OCC(C)C)=[O:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO.O>C1(C)C=CC=CC=1>[CH:3]1([O:9][CH:10]([O:12][C@H:13]([CH3:21])[CH2:14][OH:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(OC1CCCCC1)O[C@H](C)CO
Yield: 88.7 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 47.9 g (0.17 mole) of the isobutyl (R)-(+)-2-(1-cyclohexyloxyethoxy)propionate (obtained in Reference Example 7) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 41.3 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 7 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 30.5 g (yield: 88.7%) of an oily title compound (diastereomixture).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 0 °C

Procedure:
Thionyl chloride (270 mL) was added dropwise to methanol (1500 mL) over 1 hour, followed by the addition of (4R)-4-hydroxy-L-proline (150 g). The mixture was stirred at reflux for 36 hours, and then concentrated under reduced pressure. Methanol (1500 mL) was added, followed by a slow addition of triethylamine (310 mL). The mixture was cooled to 0° C., filtered, and the filtrate was concentrated to afford methyl (4R)-4-hydroxy-L-prolinate. The residue was used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15](Cl)=[CH:16][C:17]=3[Cl:21])[NH:12][C:11]2=[O:23])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>N1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[C:10]([CH3:24])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11](=[O:23])[NH:12]2
Reactant: CN1CCNCC1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc([N+](=O)[O-])cc2)C3=O)CC1
Yield: 45.5 %

Procedure:
A mixture of 3-(4-nitro-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.3 g, 0.82 mmol) and 1-methylpiperazine (123 mL, 1.23 mmol) in dry pyridine (5.0 mL) was heated at reflux temperature for 5 hours. After evaporation of the solvent in vacuo, the residue was diluted with water (100 mL), and the resulting suspension was extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL×2), dried over anhydrous MgSO4 concentrated under reduced pressure. The pure objective compound (0.16 g, 46%) was obtained as yellow solid by a flash column chromatography (CH2Cl2:MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.90 (s, 3H, CH3), 2.34 (s, 3H, NCH3), 2.54-2.59 (m, 4H, NCH2), 2.88-3.07 (m, 4H, NCH2), 6.43 (d, J=1.8 Hz, 1H, ArH), 6.64 (d, J=2.0 Hz, 1H, ArH), 7.46 (d, J=9.0 Hz, 2H, ArH), 8.17 (d, J=9.0 Hz, 2H, ArH), 8.64 (br s, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC)[CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)#[N:2].[OH-].[Na+].C1C[O:31][CH2:30]C1>O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:30])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)#[N:2]
Reactant: C1CCOC1
Reactant: CCn1c(-c2ccc(C(=O)OC)cc2)c(C#N)c2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 92 %

Procedure:
Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1Ga step B, was combined with NaOH (40 mg, 1 mmol), H2O (0.8 mL), and THF (3.4 mL) and was heated at 80° C. for 1 hour. The reaction mixture was diluted in H2O and was then ether-washed. The aqueous layer was acidified with aqueous HCl, and was extracted into EtOAc. The organic layer was dried and concentrated to yield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH:40]=[N:39]1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cn(-c2ccc(-c3cnn(C(F)F)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-(difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester (122 mg, 0.50 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (183 mg, 85% yield) as a white solid: mp 185-187° C.; NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.41 (1H, t, J=8.3 Hz), 7.03-7.48 (10H, m), 7.79 (1H, d, J=1.9 Hz), 7.83 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=0.8 Hz). LC-MS (ESD m/z 479 [M+H]+. Anal. Calcd for C24H17F3N6O2: C, 60.25; H, 3.58; N, 17.57. Found: C, 60.19; H, 3.48; N, 17.52.
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[NH:23][C:22](=[S:24])[NH:21][C:20]2=[O:25])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:26](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:17][C:14]([C:11]1[CH:10]=[C:9]([CH:18]=[C:19]2[NH:23][C:22]([S:24][CH3:26])=[N:21][C:20]2=[O:25])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)(C)C)c1O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Iodomethane (0.5 mL, 8 mmols) is added to a stirred suspension of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone (2.5 g, 7.5 mmols) and diisopropylethylamine (1.35 mL, 7.7 mmols) in ethanol (25 mL), and the mixture is stirred under an inert atmosphere at room temperature. After 5 hours the resultant solution is stirred into water (150 ml). After a hour the precipitate is filtered off, rinsed three times with water and dried to afford the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-2-(methylthio)-4H-imidazol-4-one (2.6 g), mp 248°-249° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].N[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:15]>C(#N)C>[Cl:15][C:2]([CH3:4])([CH2:3][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)C(=O)OC
Reactant: Cl
Reactant: Nc1ccccc1
Solvent: CC#N
Product: COC(=O)C(C)(Cl)Cc1ccccc1
Yield: 80 %

Procedure:
Following the general procedure of Example I, 280 mmols of distilled methyl methacrylate were reacted with 25 mmols of distilled aniline in 30 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in an 80% yield of methyl 2-chloro-2-methyl-3-phenylpropionate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][C:12](=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]3[NH:13][C:12](=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[C:9]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(2-chloroethoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:4]([O:6]CC1C=CC=CC=1)=O)[CH3:3].[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:25]([C:31]([O:33]CC1C=CC=CC=1)=O)[CH2:26][CH2:27][C:28](=[O:30])[OH:29].Cl.[NH2:52][CH2:53][C:54]([NH2:56])=[O:55]>>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@@H:2]([C:4]([NH:52][CH2:53][C:54]([NH2:56])=[O:55])=[O:6])[CH3:3].[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:25]([C:31]([NH:52][CH2:53][C:54]([NH2:56])=[O:55])=[O:33])[CH2:26][CH2:27][C:28](=[O:30])[OH:29]
Reactant: O=C(O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Product: NC(=O)CNC(=O)[C@@H](CCC(=O)O)NC(=O)OCc1ccccc1
Yield: 74 %
Yield: 86 %

Procedure:
Next, the extension of the use of the MEs to the coupling reaction of D-amino acids as acyl donor, Z-D-Phe-OBn (28), Z-D-Ala-OBn (29), and Z-D-Glu-OBn (30) with Z-L-Phe-OBn (1) was examined. While WT enzyme did not accept D-amino acids as acyl donors, all of the MEs were able to catalyze the coupling of D-amino acids with Z-L-Phe-OBn (1). Although the reactions of Z-D-Phe-OBn (28) in all cases were slow to give Z-D-Phe-Gly-NH2 (39) in low yield (the best was 14% by using M-n), peptide coupling of Z-D-Ala-OBn (29) or Z-D-Glu-OBn (30) with Gly-NH2 (31) proceeded without remaining substrates. It is noteworthy that using ME-k and -m in case of Z-D-Ala-OBn (29) and ME-o in case of Z-D-Glu-OBn (30) gave Z-D-Ala-Gly-NH2 (37, 86%) and Z-D-Glu-Gly-NH2 (38, 74%), respectively, in very high yields. Probably, the CMMs recognized D-amino acids in a different manner from L-amino acids, i.e., the carbobenzoxy group of α-position seems to bind the S1 pocket. On the other hand, repulsion between the phenylmethyl group of Z-D-Phe-OBn (28), which had the biggest substituent among the three kinds of substrate, and the other parts in the pocket of active site of the MEs could cause low reactivity of Z-D-Phe-OBn (28).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[S:22][C:13]=12.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:29]=[N:28][N:27]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:26]=3)[S:22][C:13]=12
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cn[nH]c4)sc23)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cnn(CCN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 69.5 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile (57 mg, 0.13 mmol), 4-(2-chloroethyl)morpholine hydrochloride (24 mg, 0.13 mmol), and cesium carbonate (42 mg, 0.13 mmol) in 1 mL of dimethylformamide is heated at 50° C. overnight. The mixture is cooled to room temperature and then added to water. The resulting precipitate is collected by filtration. The collected solid is purified by flash column chromatography, eluting with 1:7 methanol:ethyl acetate to provide 50 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp greater than 200° C.; 1H NMR (DMSO-d6) δ 2.44 (br s, 4H), 2.62 (t, 2H), 3.53 (br s, 4H), 3.81 (s, 3H), 4.23 (br s, 2H), 6.77 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.80 (br, 1H), 8.24 (br, 1H), 8.37 (s, 1H), 13.36 (br s, 1H); MS 553.1 (M+H)+.