Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH2:21][C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)=[O:23]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:22]([NH2:21])=[O:23])=[CH:25][CH:26]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: NC(=O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-terephthalamide was prepared starting from intermediate D and 4-(aminocarbonyl)benzoic acid. MS calcd. for C24H18ClN3O3 [(M+H)+] 431.9, obsd. 432.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 74 °C
Yield: 52.9 %

Procedure:
A solution of tert-butyl {1-[(3,4-dichlorophenyl)(1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate (364 mg, 0.75 mmol) in dry tetrahydrofuran (1 mL), under nitrogen, was treated with a solution of borane (1.0 M in tetrahydrofuran, 2.62 mL, 2.62 mmol). The reaction was heated at 74° C. for 2 h, after which time the reaction was cooled and quenched by the addition of methanol (4 mL). The solvents were removed in vacuo, and the products were purified via Biotage Horizon (FLASH 25 M, silica, gradient from 10% EtOAc/hexane to 90% EtOAc/hexane) to yield 187 mg (53%) tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate as a white foam which eluted first and 88 mg (31%) 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol as a colorless oil which eluted second. tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate: MS (ES) m/z 471.3 ([M+H]+); HRMS: calcd for C24H36Cl2N2O3, 470.2103; found (ESI), 471.2165. 1-{1-(3.4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol: MS m/z 385/387/389 ([M+H]+). 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol was converted to the dihydrochloride salt with a methanolic solution of hydrochloric acid and diethyl ether to yield 45 mg (41%) 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H30Cl2N2O.2.00 HCl, 456.1269; found (ESI), 385.183.
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl-].[CH2:10]([NH2:12])[CH3:11]>C1C=CC=CC=1>[C:1]1([C:6]([NH:12][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)C1=CCCC1
Reactant: CCN
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCNC(=O)C1=CCCC1
Temperature: 30 °C
Reaction time: 10 h
Yield: 69.8 %

Procedure:
N-Cyclopentenoyl-ethylamine was prepared from cyclopentenoic acid (2 grams, 17.5 mmol) and oxallyl chloride (2.2 grams, 17.5 mmol) after stirring at 25-35° C. for 8-12 hours. To this was added a benzene solution of ethylamine (2.1 grams, 48.7 mmol) at 0° C., and this reaction mixture was stirred for 3 hours at 25-35° C., after which time the solvent was evaporated under vacuum to yield N-cyclopentenoyl-ethylamine (1.7 grams), yield: 68.9%. A solution of N-cyclopentenoyl-ethylamine (1.7 grams, 13.3 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) under a nitrogen atmosphere, and lithium aluminum hydride (LiAlH4; 1.3 grams, 36.1 mmol) was added to the solution. After being stirred for 1 hour at 25-35° C., the reaction mixture was gently refluxed for 8 hours. The reaction mixture was quenched with saturated sodium sulfate solution, filtered, and the precipitate washed with diethyl ether (Et2O). The filtrate was concentrated to afford N-cyclopentylmethyl ethylamine (0.6 g, yield: 40%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=O)[CH2:17][C-:18]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[C:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])=[C:19]1[C:35]([CH3:38])([CH3:37])[CH3:36].[CH-:40]1[CH:44]=[CH:43][CH:42]=[CH:41]1.[Fe+2:45].O>CCOCC.CCCCCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C-:18]1[C:19]([C:35]([CH3:36])([CH3:37])[CH3:38])=[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:21]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:22]1[C:23]([CH3:26])([CH3:25])[CH3:24].[CH-:40]1[CH:44]=[CH:43][CH:42]=[CH:41]1.[Fe+2:45]
Reactant: CC(C)(C)c1c(C(C)(C)C)c(C(C)(C)C)[c-](CC(=O)CCCCBr)c1C(C)(C)C
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1c(C(C)(C)C)c(C(C)(C)C)[c-](CCCCCCBr)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
First, 2.27 g (17.02 mmol) of AlCl3 was dissolved in 200 ml of dry Et2O in a Schlenk flask under controlled, positive nitrogen pressure. Second, the solution was cooled to 0 degrees centigrade and 17.0 g (17.0 mmol) of 1.0 M LiAlH4 was charged into the flask via syringe. The resulting suspension was warmed to room temperature and agitated for approximately 15 minutes. Next, 10.00 g (17.02 mmol) of the above prepared 6-bromo-1-(tetra-tert-butylferrocenyl)-2-hexanone was slowly added to the suspension. Once the addition of the ketonic product was complete, the solution was heated to reflux for approximately 3 hours, after which time the solution was cooled to room temperature. The reaction was then quenched by slowly adding H2O to the solution. When no further exothermic reaction was observed, 250 ml of H2O was added to dilute the solution. The solution was then transferred to a separatory funnel, whereupon the organic layer was collected and the aqueous layer was extracted with 100 ml of Et2O. The organic portions were combined and then washed with NaHCO3 and brine. Next, the solution was dried over MgSO4. The solution was then decanted from the drying agent and filtered. Next, the solvent was removed via rotary evaporation yielding a yellow-orange oil. The oil was dissolved in a small amount of hexane, applied to a vacuum assisted gel column, and eluted with more hexane. Upon solvent removal, 8.73 g of 6-bromo-1-(tetra-tert-butylferrocenyl)hexane was isolated as a yellow-orange solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+]>[C:8]1([S:14]([NH:1][CH:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CO)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
DL-serine (1.051 g) was dissolved in a 1 M aqueous NaOH solution (20 ml). Benzenesulfonyl chloride (1.77 g) was added at 0° C. After 30 min the ice bath was removed and the mixture was stirred for 18 h at room temperature. The mixture was again placed in an ice bath. The mixture was acidified to pH 1 using 25% aqueous HCl. The colorless precipitate was collected by filtration, washed with 1 M HCl and dried to give (RS)-2-benzenesulfonylamino-3-hydroxy-propionic acid (1.23 g) as a colorless solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:26]([OH:28])=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>Cl.CC(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:26]([OH:28])=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Yield: 140.7 %

Procedure:
In 90.8 ml of 2N HCl/AcOH, 22.8 g (36.3 mmol) of BOC-Leu-Lys(Z)-CHA was dissolved and reacted at room temperature for 2 hours. After the reaction, deposited crystals were reprecipitated in 1000 ml of ether, filtered and dried to yield 20.1 g (98.0%) of H-Leu-Lys(Z)-CHA.HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:19]([N:6]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc2c(c1)[nH]c1cc(OC)ccc12
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCn1c2cc(OC)ccc2c2ccc(OC)cc21
Yield: 90.6 %

Procedure:
A 50 mL flask was charged with 3.00 g (13.2 mmol) of compound 12, 5.10 g (26.4 mmol, Aldrich Co.) of 1-bromooctane, 1.06 g (26.4 mmol) of sodium hydroxide reagent grade, 134 mg (0.39 mmol) of tetrabutylamonium hydrogensulfate (TBAH) and 25 mL of anhydrous acetone. The resulting mixture was refluxed under argon for 24 h and then poured into 100 mL of distillated water. The aqueous layer was extracted three times with diethyl ether. The combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes as eluent) to provide 4.06 g of the title product as white fluffy solid. M.P. 63-64° C. (Yield: 91%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C:65]1([C:70]([NH:72][C:73]2[CH:78]=[CH:77][C:76](/[CH:79]=[CH:80]/[C:81]([O:83]CC)=[O:82])=[CH:75][CH:74]=2)=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66]1.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.C1COCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:64][C:65]4([C:70]([NH:72][C:73]5[CH:74]=[CH:75][C:76](/[CH:79]=[CH:80]/[C:81]([OH:83])=[O:82])=[CH:77][CH:78]=5)=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)NC3(C(=O)Nc4ccc(/C=C/C(=O)O)cc4)CCCC3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A solution of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Step 6) in DMF (0.1 M) was treated with DIPEA (2 eq.), HATU (1.1 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (from Step 7, 1.1 eq.). The solution was stirred at 25° C. for 12 h, then for 24 h at 50° C. The mixture was diluted with EtOAc, and then washed sequentially with HCl (2×, 1 N), NaOH (2×, 1N) and brine. The organic layer was dried over Na2SO4 and concentrated to afford an oil, which was dissolved in a mixture of THF and MeOH (0.5M, 2:1, v/v). NaOH (2 eq., 1 N) was added and the resultant mixture stirred at 50° C. for 1 h. The reaction mixture was diluted with EtOAc, and then washed with HCl (2×, 1 N), brine, and dried over Na2SO4. Evaporation gave an off-white foam, which was purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min) to give the title compound (45%) as a white powder after lyophilization. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.11-1.39 (m, 3H), 1.60-1.96 (m, 11H), 2.03-2.17 (m, 2H), 2.28-2.40 (m, 2H), 2.61 (m, 1H), 2.81 (s, 3H), 2.88 (s, 3H), 4.84 (s, 2H), 6.40 (d, J 16.0, 1H), 7.32 (d, J 6.4, 2H), 7.46-7.55 (m, 4H), 7.59 (d, J 8.4, 2H), 7.65 (d, J 8.4, 2H), 7.71 (d, J 8.2, 1H), 7.80 (d, J 8.2, 1H), 7.86 (s, 1H), 8.27 (s, 1H), 9.67 (s, 1H), 12.1 (bs, 1H). MS (ES+) m/z 661 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([CH2:9][C:10](N(C)C)=[O:11])[CH2:8][CH2:7]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([CH3:28])[CH:24]=[CH:25][C:26]=2[CH3:27])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl.O.C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]([CH3:28])[C:24]([C:10](=[O:11])[CH2:9][CH:6]3[CH2:7][CH2:8]3)=[CH:25][C:26]=2[CH3:27])=[CH:20][CH:21]=1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Reactant: CN(C)C(=O)CC1CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
POCl3 (1.36 g, 0.82 ml, 8.88 mmol) was added to 2-cyclopropyl-N,N-dimethylacetamide (prepared according to the procedure described in Nils SchrOder et al., J. Am. Chem. Soc., 2012, 134, 8298-8301), 1.13 g (8.88 mmol) at 0° C. and under stirring and the reaction was continued at 0° C. for 15 min. The reaction mixture was allowed to warm up to room temperature, stirred for 20 min, and diluted with 1,2-dichloroethane (10 ml). 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure described in Kazuhiko Taguchi et. al., Tetrahedron Letters, 2005, 46, 4539-4542) (1.64 g, 8.0 mmol) was dissolved in 1,2-dichloroethane (20 ml) and was added to the reaction mixture at 0° C. The reaction mixture was heated to reflux temperature (95° C.) for 30 min. The progress of the reaction was monitored TLC. The reaction mixture was cooled to room temperature. Sodium acetate (4.01 g, 48.9 mmol) was dissolved in water (15 ml) and added to the reaction mixture. The reaction mixture was stirred at 100° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with DCM (50 ml) and water (20 ml) was added to it. The organic layers were separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. This crude product was purified by column chromatography using 5-10% ethyl acetate in hexanes as an eluent to obtain the title compound 3(0.77 g, 30.5%). MS: m/z 288 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([CH:28]=2)[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[S:3]1.[H][H]>CN(C)C=O.[C].[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([CH:28]=2)[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[S:3]1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Yield: 217.2 %

Procedure:
0.55 g of N1-(5-[(2,4-dioxo-1,3-thiazolane-5-ylidene)methyl]-2-methoxybenzyl)-4-(trifluoromethyl)benzamide was suspended in 20 ml N,N-dimethylformamide, and 0.60 g of 10% palladium-carbon was added, and the mixture was stirred at 50° C. under pressure at 15 kg/cm2 hydrogen for 16 hours. After the reaction, the catalyst was filtered off, and after the solvent was evapoarated. Water was added to the residue, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (1:1), 1.2 g of N1-{5-[(2,4-dioxo-1,3-thiazolane-5-yl)methyl]-2-methoxybenzyl}-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].C1C2C(=CC=CC=2)C=CC=1O.[C:24](=[O:26])=[O:25]>O>[OH:11][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: [O-]c1ccc2ccccc2c1
Agent: Oc1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1O
Reaction time: 3 h

Procedure:
A finishing treatment was carried out continuously, while employing the facilities as shown in the drawing. On an hourly basis, 83 kg of sodium 2-naphtholate, 42 kg of 2-naphthol and 166 kg of a mixture of hydrogenated triphenyls were fed to a stirring tank 1, followed by stirring and suspension. The resulting suspension mixture was supplied at a rate of 291 kg/hr to a reaction vessel 2 maintained at a carbon dioxide pressure of 6 kg/cm2 (G), and a reaction was allowed to proceed at 260° C., with the residence time being kept at 3 hours. The reaction mixture flowing out of the reaction vessel 2 was cooled with a heat exchanger 3, and mixed with water fed at a rate of 420 1/hr in a stirring tank 4, and the resulting mixture was regulated at a temperature of 85° C. and transferred to a separating tank 5, followed by separation into the reaction medium layer and the water layer at 85° C. From the upper reaction medium layer, the 2-naphthol was recovered as sodium naphtholate with use of a recovery apparatus (not shown in the drawing). The lower water layer was adjusted in a pH adjusting tank 6 to a pH 5.5 with dilute sulfuric acid and transferred to an extractor 7, where the 2-naphthol and tar were extracted with 2000 liters of xylene. From the xylene layer, there were recovered the xylene and 2-naphthol by use of a vacuum distillation apparatus (not shown in the drawing). The water layer flowing out of the extactor 7 was transferred to an acid precipitation tank 8, and adjusted to a pH 2.0 with dilute sulfuric acid at 85° C. to perform acid precipitation, whereby there was produced 2-hydroxynaphthalene-3-carboxylic acid at a rate of 44.8 kg/hr. The yield based on sodium 2-naphtholate was 47.7%, and 2-naphthol was recovered at a rate of 37.3 kg/hr, with the selectivity being 99.4%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1>CN1CCCC1=O>[NH2:33][C:29]1[CH:28]=[C:27]([NH:34][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:32]=[CH:31][CH:30]=1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(N)c1
Yield: 50.4 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), 1,3-phenylenediamine (288 mg), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave device at 200° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added thereto for extraction. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1), and was washed with ethyl acetate to obtain 5-[(3-aminophenyl)amino]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (120 mg).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6])C.Cl>CC(C)=O.O>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5](=[O:6])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1cccs1

Procedure:
The thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb may be subjected to hydrolysis to provide the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb. The hydrolysis may be carried out under either acidic or basic conditions. Basic hydrolysis can typically be carried out by treating a solution of a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb (1.0 equivalent) in an aqueous mixture of an appropriate solvent such as methanol, tetrahydrofuran or 1,4-dioxane with a suitable base such as aqueous sodium hydroxide or potassium hydroxide (typically 1.5 equivalents) for a period of four to twenty hours at a temperature range of 0° C. to room temperature. The reaction mixture can be worked up by acidification with an appropriate acid such as hydrochloric acid or acetic acid followed by extraction with an appropriate solvent such as ethyl acetate or dichloromethane. The resulting organic layer may then be concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa or IVb, respectively. If desired, the thiophenyl oxo-acetic acid IV, IVa or IVb could then be further purified by recrystallization or preparative HPLC. Alternatively, the hydrolysis of the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb to the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb may be carried out under acidic conditions. The acidic hydrolysis is typically carried out by refluxing a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb in a mixture of acetone and water in the presence of hydrochloric acid for one to four hours. The reaction mixture is then extracted with an appropriate solvent such as dichloromethane and the organic layer concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa and IVb, respectively.
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][O:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[Si:27]([O:15][CH2:14][CH:2]([OH:1])[CH2:3][O:4][CH2:5][P:6](=[O:13])([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CCOP(=O)(COCC(O)CO)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(COCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Yield: 71.2 %

Procedure:
To a solution of diethyl 2,3-dihydroxypropoxymethylphosphonate (4.15 g, 17.lmmol), triethylamine (1.9 g, 2.62 ml, 18.81 mmol), 4-dimethylaminopyridine (84mg, 0.7 mmol) and t-butyldimethylchlorosilane (2.92 g, 19.4 mmol) in dichloromethane (50 ml) was stirred for 16 hours at 20° C. under nitrogen. The solution was washed with water (50 ml), saturated ammonium chloride (50 ml) and dried (Na2SO4). The solvents was evaporated to leave a yellow oil which was chromatographed on silica eluting with ethyl acetate affording diethyl 3-t-butyldimethylsilyloxy-2-hydroxypropoxymethylphosphonate (4.35 g, 71%) as a pale lemon liquid. νmax (film) 3400, 1460 , 1240, 1100, 1020 and 960 cm-1 ; δH (CDCl3) 0.05(6H, s, (CH3)2Si), 0.86(9H, s,(CH3)3C), 1.31(6H, t, J7.3 Hz, 2×CH2CH3), 2.50 (1H, br.s, D2O exchangeable, OH), 3.70(7H, m, CH2OSi+CHOH+CH2OCH2P), 4.12(4H, m, 2×CH2CH3); m/z 357(MH+,3%), 341 (M-CH3+,4%); Found: C,46.89; H,9.23%; C14H33O6PSi requires C,47 17; H,9.33%