Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5](=[NH:21])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:20])(=[O:19])[NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:8][CH:7]=1)C.[NH3:22]>>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:13][S:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]([NH2:21])=[NH:22])=[CH:11][CH:10]=1)(=[O:19])=[O:20]
Reactant: CCOC(=N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: N
Agent: Cl
Product: N=C(N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(thiazol-2-ylsulfamoyl)-benzimidic acid ethyl ester hydrochloride (100 mmol) in 7 N NH3 (120 mL in methanol) was stirred at 60° C. for 2 h. After reaction mixture was cooled to room temperature, the precipitate was filtered, washed with methanol, and dried in vacuo to give a quantitative yield of 4-(thiazol-2-ylsulfamoyl)-benzamidine.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:17][N:16]=2)[CH:10]=[CH:11][C:12]=1[O:13]C)#[N:6]>ClCCl>[C:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:17][N:16]=2)[CH:10]=[CH:11][C:12]=1[OH:13])#[N:6]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)ns1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(O)c(C#N)c2)ns1
Reaction time: 1 h

Procedure:
Under ice-cooling, boron tribromide was added to a dichloromethane solution of ethyl 3-(3-cyano-4-methoxyphenyl)isothiazole-5-carboxylate, followed by stirring for 1 hour and then stirring at 40° C. for 3 hours to obtain ethyl 3-(3-cyano-4-hydroxyphenyl)isothiazole-5-carboxylate. AP: 297.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[N+]([O-])([O-])=O.[C:29]1([NH:35][C:36]([NH2:38])=[NH2+:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:7]([C:5]3[CH:4]=[CH:3][N:38]=[C:36]([NH:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:37]=3)=[C:15]3[N:10]([N:11]=[CH:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:21][CH:20]=1
Reactant: NC(=[NH2+])Nc1ccccc1
Reactant: COc1ccc(-c2nn3ncccc3c2C(=O)/C=C/N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3ncccc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 120 °C
Reaction time: 28 h
Yield: 30 %

Procedure:
To a solution of 100 mg (0.31 mmol) of (2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)pyrazolo[1,5-b]pyridazin-3-yl]prop-2-en-1-one in 5 ml of N,N-dimethylformamide were added 103 mg (0.39 mmol) of N-phenylguanidinium nitrate and 153 mg (1.11 mmol) of potassium carbonate. The mixture was stirred at 120° C. for 28 hours. Removal of solvent followed by column chromatography with dichloromethane:methanol=100:1 gave the crude product. The crude product was washed with dichloromethane to afford the desired compound in 30% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([NH:16][C:30](=[O:31])[C:29]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:28]=1[CH3:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(I)cc2)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
1.5 g (4.32 mmol) of (1) and 2.9 ml (17.3 mmol) of DIPEA were dissolved in 15 ml of DCM and cooled to 0° C. 1.73 g (9.51 mmol) of 2,4,6-trimethylbenzoyl chloride were added and the solution was stirred at room temperature for 3 h. The solution was poured into saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate. The organic layer was extracted with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 1.83 g of (2).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]1=[O:25]>C(Cl)Cl>[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:19][C:18]1=[O:25]
Reactant: Cc1cc(O)cc(=O)n1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(=O)n1C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (0.85 ml, 5 mM) was added dropwise to a stirred solution of 1,6-dimethyl-4-hydroxypyridin-2-one [0.7 g, 5 mM] (obtainable as described by Castillo et al., Bull. Soc. Chim. France, 1982, 257) in dry methylene chloride (15 ml). The resulting solution was kept at room temperature for 18 hours, washed with aqueous sodium carbonate solution, dried (MgSO4) and the solvent evaporated. The residual solid was purified by flash chromatography (Merck 9385) using ether as eluant to give 1,6-dimethyl-4-(trifluoromethanesulphonyloxy)-2-pyridone as a solid (0.67 g), m.p. 65°-67° C.; NMR: 2.41(3H,s, CH3) 3.53(3H,s, NCH3), 6.05(1H,s, CH), 6.38(1H,s, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)\[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1cccc(F)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.58 (s, 1H), 7.42 (m, 3H), 7.15 (m, 3H), 7.05 (s, 1H), 3.80 (m, 2H), 3.40 (m, 2H), 3.30 (m, 4H), 3.05 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:33])=[C:13]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:33])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a solution of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 10.3 mmol) in dichloromethane (100.0 mL) were added trifluoroacetic acid (12.9 g, 113.2 mmol) and triethylsilane (13.2 g, 113.2 mmol). The reaction mixture was stirred at ambient temperature for 4 h, then concentrated in vacuo to dryness. The gummy residue was diluted with ethyl acetate (100.0 mL), washed with water (3×100.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.90 g, 61%) as a colourless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ9.11 (s, 1H), 7.3-7.27 (m, 5H), 7.18 (dd, J=7.5, 7.5 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 7.06 (dd, J=7.9 Hz, 1H), 6.97-6.86 (m, 3H), 6.79-6.68 (m, 3H), 5.04 (ABq, 2H), 4.91 (s, 2H), 4.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ175.9, 151.5, 149.7, 142.8, 138.8, 137.8, 130.2, 128.8, 128.2, 128.1, 128.1, 128.0, 127.4, 126.8, 125.2, 124.2, 122.7, 117.6, 117.6, 116.3, 114.9, 109.1, 70.2, 48.1, 38.6; MS (ES+) m/z 464.3 (M+1), 462.3 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH:24]=1.Cl.[OH-].[Na+]>C(OCC)C.O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:33]2([OH:36])[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[C:27]([CH3:29])[N:26]=3)[CH2:35][CH2:34]2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: Cc1cc(C)nc(N2CCC(=O)CC2)c1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CCC(O)(c3ccc(N)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
n-Butyl lithium (1 mL, 1.6 M in hexane, 1.6 mmol) was added dropwise to a solution of 2-(4-bromo-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.7 g, 2.20 mmol) in dry diethyl ether (10 mL) and stirred at room temperature for 15 min then cooled in an ice bath. A solution of 4′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (0.3 g, 1.47 mmol) in dry tetrahydrofuran (15 mL) was added and the resulting mixture heated at 50° C. for 2.5 h. The reaction mixture was brought to room temperature and stirred overnight, then cooled to 0° C. and quenched into ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the crude compound, to which was added 2N HCl and the resulting mixture was stirred overnight at room temperature. The pH of the solution was adjusted to pH 10 with dilute sodium hydroxide then the mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a viscous red oil which was purified by washing with pentane (5×10 mL) to afford 4-(4-amino-phenyl)-4′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-ol (0.25 g, 57%).
Reaction SMILES: [F:1][CH:2]([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:36][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)F)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Yield: 62.2 %

Procedure:
To a microwave vial containing (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.098 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.015 mL, 0.147 mmol) followed by K2CO3 (14 mg, 0.098 mmol). The resulting mixture was subjected to microwave irradiation for 1 h at 200° C. after which time the reaction was quenched with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material which was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.061 mmol, 62% yield). LC/MS (m/z, M-H): 493.5
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28].O>O1CCCC1>[Cl:25][C:26]([Cl:31])([Cl:30])[C:27]([NH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:5])=[O:28]
Reactant: COc1cccc(C(=O)c2ccccc2N)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccccc2NC(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 2.89 g (12.7 mmol) of 2-amino-3′-methoxybenzophenone and 2.13 ml (15.2 mmol) of triethylamine in 16 ml of tetrahydrofuran (THF), 1.56 ml (14 mmol) of trichloroacetyl chloride were added dropwise under ice-cooling and stirred for 2 hours. Water was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give 4.51 g (12.1 mmol) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:31]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 1.00 g (3.36 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 1.00 g (9.91 mmol) of triethylamine, and 35 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether. The crude product was suspended in 20 mL of 6M hydrochloric acid and 20 mL of glacial acetic acid and was heated at 60° C. for 2 hours. The solution was concentrated to an oil which was triturated with isopropanol. The solid was collected by filtration and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, mp>300° C.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([C:13](OC)=[O:14])[CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([CH2:13][OH:14])[CH:3]=1
Reactant: COC(=O)c1cc(O)n2nc(CO)nc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(O)n2nc(CO)nc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
In 4 liters of ethanol was suspended 48.94 g of 7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine, and 33 g of sodium borohydride was added little by little thereto and then the mixture was stirred at room temperature for 3 hours and then refluxed for 4 hours. A residue obtained by removing ethanol was dissolved in 2 liters of water, and 500 ml of Amberlite IRC-50 (H+) (trade name) was added thereto and stirred. Subsequently, the mixture was filtered and after removing water from the filtrate, 500 ml of methanol was added to the filtrate and the mixture was stirred. Then, methanol was removed from the mixture to obtain a residue. These procedures were repeated three times. Then, 500 ml of ethanol was added to the residue and the mixture was condensed. Precipitated crystal was collected by filtration, washed with ethanol and dried to obtain 39.35 g of the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.CC(O)=O.CNC>CC(O)C>[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(C)=O
Agent: CNC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccc(Cl)cc1Cl)C(C)=O
Temperature: 40 °C

Procedure:
To a stirred solution of methyl acetoacetate (345 mg, 2.97 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) in 2-propanol (5 mL) was added AcOH (7 mg, 0.11 mmol) and dimethylamine (0.06 mL, 2M in THF, 0.11 mmol). The reaction was heated to 40° C. for 4 hrs followed by cooling to ambient temperature for 15 hrs. The reaction was concentrated and purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate as a mixture of two isomers (colorless oil, 610 mg, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(OCc2ccccc2)cn1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ncc(OCc2ccccc2)cn1
Yield: 96982.2 %

Procedure:
A solution of 5-(benzyloxy)pyrimidin-2-amine (60.0 g, 0.30 mmol) in dichloromethane (400 mL) was added with pyridine (30 mL, 0.37 mmol), the mixture was added dropwise with a solution of hexanoyl chloride (46.0 g, 0.34 mmol) in dichloromethane (100 mL) with stirring on an ice bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with 1 M hydrochloric acid (500 mL), and extracted with chloroform, and the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was recrystallized from chloroform-hexane to obtain N-[5-(benzyloxy)pyrimidin-2-yl]hexanamide (87.1 g, 98%) as colorless needles.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([C:39](OC)=[O:40])[C:32](=[CH:37][CH:38]=4)[C:33](OC)=[O:34])[CH:21]=3)=[C:16]([CH2:43][CH2:44][CH3:45])[CH:15]=2)[O:13][CH2:12][CH2:11][O:10]1)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([C:9]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:32]([CH2:33][OH:34])=[C:31]([CH2:39][OH:40])[CH:30]=4)[CH:21]=3)=[C:16]([CH2:43][CH2:44][CH3:45])[CH:15]=2)[O:10][CH2:11][CH2:12][O:13]1)[CH3:8]
Reactant: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(CCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
182 mg (4.8 mmol) of lithium aluminum hydride are placed in 20 ml of dry THF in a round-bottomed flask and under nitrogen. At 0° C., a solution of 640 mg (1.2 mmol) of dimethyl 4-{2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}phthalate in 5 ml of THF is added dropwise. The reaction medium is stirred for 1 hour at room temperature. 200 μl of water are then added very slowly, followed by addition of 200 μl of 15% sodium hydroxide solution and then 600 μl of water. The medium is filtered and the filtrate is evaporated to dryness. 640 mg (100%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)=[O:4].[OH-].[Na+].Cl>C(O)C>[CH2:15]([N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]1=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1c2c(cc(C(=O)OC)c1=O)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCn1c2c(cc(C(=O)O)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid methyl ester (1-015-02) (263 mg, 1 mmol) was dissolved in ethanol (6 mL), and to the reaction mixture was added an aqueous solution of sodium hydroxide (2 mol/L, 0.6 mL, 1.2 mmol), and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added diluted hydrochloric acid (0.4 N, 6 mL) and the reaction mixture was extracted with ethyl acetate (25 mL). To the aqueous layer was added sodium chloride, followed by extraction with ethyl acetate (25 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crystal residue was recrystallized from hexane to give 1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (4-002-01) (220 mg, 88%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][S:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCSCC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCSCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 38 %

Procedure:
1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.67 g) and 5-amino-2-(4-thiomorpholinopiperidin-1-yl)benzonitrile (0.8 g) were added to pyridine (10 ml) and the reaction was conducted for 1 h at room temperature. To the reaction mixture was added aqueous potassium carbonate solution and the precipitated crystals were recrystallized from hydrous dimethylformamide to give the title compound (0.52 g), melting point: 256° C./decomposition.