Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH:57]([CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH2:58][CH2:59][CH3:60])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:62]2[CH2:61][CH:57]([CH2:58][CH2:59][CH3:60])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:69][CH:68]=1
Reactant: CCCC(CNCc1ccc(F)cc1)C(=O)OCC
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 39.7 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.096 g, 0.272 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.114 g, 0.300 mmol) and 4-methylmorpholine (0.060 mL, 0.546 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-pentanoic acid ethyl ester (0.073 g, 0.273 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 19 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (12 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.531 mL, 1.64 mmol) was added and the reaction mixture was heated to 70° C. for 48 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-5-propyl-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.060 g, 0.108 mmol, 39%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.75 (3H, t, J=7.1 Hz), 1.08-1.19 (2H, m), 1.21-1.28 (1H, m), 1.47-1.55 (1H, m), 2.53 (1H, bs), 2.95 (3H, s), 3.18 (1H, dd, J1=3.8 Hz, J2=13.2 Hz), 3.55 (1H, dd, J1=4.5 Hz, J2=12.9 Hz), 4.24 (2H, d, J=6.5 Hz), 4.39 (1H, d, J=14.7 Hz), 4.79 (1H, d, J=14.7 Hz), 7.14-7.18 (2H, m), 7.23 (1H, s), 7.36-7.39 (2H, m), 7.63 (1H, t, J=5.9 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.3 [M+H+].
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH:3]([CH3:5])[CH3:4].[CH2:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19]Cl)[CH3:15]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][CH3:22])[CH2:14][CH3:15])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)COc1ccccc1O
Reactant: CCN(CC)CCCCl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCCOc1ccccc1OCC(C)C

Procedure:
The compound was prepared as directed in Example 1, using sodium (1.15 g; 50 mole), o-isobutoxyphenol (8.30 g; 50 mmole) and 3-diethylaminopropylchloride (7.50 g; 50 mmole) in 150 ml of ethanol. Yield 8.85 g (63%) of product, boiling at 104°-106° C under a pressure of 0.003 mm Hg, nD25 : 1.4914.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[N:7]=1
Reactant: OC1CCCCC1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2nc(N)nc(OC3CCCCC3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 299 (M+H+, 50), 217 (M+H—C6H10+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH3:21][N:22]([CH3:27])[CH2:23][C:24](O)=[O:25].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][C:24](=[O:25])[CH2:23][N:22]([CH3:27])[CH3:21])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of compound 57 (0.5 mmol) in anhydrous DMF was added dimethyl glycine (0.75 mmol) and EDC (0.75 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water, and brine, then dried with MgSO4. The Solvents were removed to afford a colorless oil, which was recrystallized in EtOAc/Hexanes to afford an off-white solid 59 in 30% yield. MS (ES+): 352; MP: 227-230° C.; 1H-NMR (CDCl3, 400 MHz): 10.15 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0 and 1.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.53 (dd, J=8.0 and 1.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.21 (s, 2H), 3.26 (s, 2H), 2.37 (s, 6H); Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.86; N, 11.96. Found: C, 64.95; H, 4.78; N, 12.14.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[CH:26]1([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:33](=[O:34])[CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C(Cl)CC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To an ice cold suspension of NaH (13 mg, 340 μmol) in DMF (5 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (100 mg, 310 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of cyclohexyl-acetyl chloride (50 μl, 340 μmol; [23860-35-7]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (8 mg, 20 μmol; 6%) as yellow oil. MS: m/e=450.0 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=[CH:18]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>>[C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20]([C:23]([Cl:28])=[O:25])[CH:19]=[CH:18]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)O)cc12
Product: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)Cl)cc12
Reaction time: 1 h

Procedure:
5 mmol of the product obtained in Step C are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is evaporated off under reduced pressure to yield the title product.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](N)=[O:8].Cl.[OH2:31]>>[CH3:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:31])=[O:8]
Reactant: O
Reactant: CCCCCCCCCCCCC(C)CNc1cc(C)c([N+](=O)[O-])cc1C(N)=O
Agent: Cl
Product: CCCCCCCCCCCCC(C)CNc1cc(C)c([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 21.9 grams 2-methyltetradecylamino-4-methyl-5-nitrobenzamide, 60.0 ml water, and 90.0 ml concentrated HCl was heated with stirring at reflux temperature for 16 hours, and then cooled, filtered, washed with water and vacuum dried. The crude product was digested with hot petroleum ether (b.p. = 70-100°), which was cooled and filtered, and the filter cake dried in air overnight. The product was recrystallized from a 3:1 ethanol-water mixture and then recrystallized again from petroleum ether (b.p. 90-100°). Yield = 13.3 grams. m.p. = 98-100°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]=1[OH:15])[O:7][CH2:8][CH2:9][CH2:10][Br:11])(=[O:3])[CH3:2].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:11].[C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[C:14]=1[OH:15])[O:7][CH2:8][CH2:9][CH2:10][P+:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1cc(OCCCBr)cc(C(C)=O)c1O
Product: CCCc1cc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(C(C)=O)c1O
Product: [Br-]

Procedure:
The title compound is prepared analogously to Example 1c) from 3-(3-acetyl-4-hydroxy-5-propylphenoxy)-propyl bromide and triphenylphosphine; m.p. 103°-105°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]([CH3:29])=[CH:22][C:23]=1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=O>>[CH3:29][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (42 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([OH:7])[CH2:5][O:6][C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
50 mmol of 1a was treated for 12 hours with 60 mmol of trityl chloride and 120 mmol of triethylamine in 150 ml of boiling toluene. After conventional working up, the remaining oil was chromatographed (Flash chromatography, eluent chloroform) and gave 2a (yield 85%) m.p. 45° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:24][O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][N:14]1[CH:21]=[C:20]([CH:22]=[CH2:23])[C:18](=[O:19])[NH:17][C:15]1=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].O.[Br:39]N1C(=O)CCC1=O>COCCOC>[C:26]([O:25][CH2:24][CH:11]([CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][N:14]1[CH:21]=[C:20]([CH:22]([N:34]=[N+:35]=[N-:36])[CH2:23][Br:39])[C:18](=[O:19])[NH:17][C:15]1=[O:16])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: [N-]=[N+]=[N-]
Reactant: C=Cc1cn(CCC(COC(=O)c2ccccc2)COC(=O)c2ccccc2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: [N-]=[N+]=NC(CBr)c1cn(CCC(COC(=O)c2ccccc2)COC(=O)c2ccccc2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A mixture of 22 (510 mg, 1.14 mmol), saturated solution of sodium azide in water (300 mg, 4.6 mmol), N-bromosuccinimide (223 mg, 1.25 mmol) and 1,2-dimethoxyethane (50 ml) was stirred at 0° C. for 30 min. Removal of the solvent in vacuo gave a viscous oil which was purified by silica gel column chromatography. Elution with chloroform-methanol (96:4, v/v) yielded 23 (530 mg, 81.5%) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]([CH3:29])[CH:26](N)[CH3:27].C[N:31](C=O)C>O>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH:12]=3)[CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(N)N(C)C
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCN(C)C)cc21
Temperature: 100 °C
Yield: 85 %

Procedure:
To a solution of Example A3 (1.00 g, 2.84 mmol) in DMF (10 mL) was added N,N-dimethylethanediamine (0.250 g, 2.84 mmol) and the resulting reaction mixture was heated at 100° C. for 36 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), and the solvent evaporated. The residue was crystallized from IPA to provide 3-(5-amino-2-chloro-4-fluorophenyl)-7-(2-(dimethylamino)ethylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.98 g, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.64 (s, 1H), 7.17 (d, J=11 Hz, 1H), 6.84 (m, 1H), 6.72 (d, J=9 Hz, 1H), 6.37 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.40 (m, 2H), 2.41 (t, J=6 Hz, 2H), 2.20 (s, 6H), 1.18 (t, J=6 Hz, 3H); MS (ESI) m/z: 404.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH4+:24]>C(O)C>[CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: CNCc1cccc(-c2nc3cccc(C(=O)OC)c3o2)c1
Solvent: O
Solvent: CCO
Product: CNCc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Methyl 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (80 mg, 0.27 mmol) and ammonium water (75.7 mg, 2.16 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (16 mg, yield 21%). 1H-NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 4.29 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.70-7.74 (m, 1H), 7.81-7.83 (d, J=8 Hz, 1H), 7.90-7.98 (m, 3H), 8.34-8.43 (m, 2H), 9.06 (s, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:19]([N:26]1[CH:31]=[C:30]([CH2:32][CH2:33][CH3:34])[C:29](=[O:35])[N:28]([CH2:36][CH2:37][CH2:38][Cl:39])[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:39].[CH2:19]([N:26]1[CH:31]=[C:30]([CH2:32][CH2:33][CH3:34])[C:29](=[O:35])[N:28]([CH2:36][CH2:37][CH2:38][N:14]2[CH2:15][CH2:16][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]2)[C:27]1=[O:40])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCc1cn(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: CCCc1cn(Cc2ccccc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-benzyl-3-(3-chloropropyl)-5-propyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-propyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 178° C.; Anal.: Calcd. for C29H35F3N4O3.HCl: C, 59.03; H, 6.32; N, 9.49%; Found: C, 59.08; H, 6.26; N, 9.52%;
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.CN(C)C=O>C(Cl)Cl>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:12])[CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(NCCN)c2ccccc2n1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(NCCNCC(O)COc2ccccc2)c2ccccc2n1
Reaction time: 48 h

Procedure:
A solution of 4.4 g. phenyl glycidyl ether and 12 g. 2-methyl-4-(2-aminoethylamino)-quinoline in 60 ml. dimethylformamide is left to stand for 48 hours at ambient temperature. The reaction mixture is then taken up in methylene chloride, washed with water, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanoltriethylamine (26:3:0.6 v/v/v), and then recrystallized from isopropyl alcohol. There are obtained 3.5 g. (34% of theory) of the desired product in the form of colorless crystals; m.p. 151°-152° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].[CH:10]1[CH:15]=C[NH+]=CC=1.[Br:16][Br-]Br>C(O)(=O)C>[Br:16][CH:3]([CH:2]([CH3:9])[CH3:1])[C:4](=[O:8])[C:5]([O:7][CH2:15][CH3:10])=[O:6]
Reactant: c1cc[nH+]cc1
Reactant: CC(C)CC(=O)C(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(Br)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
To a solution of 4-methyl-2-oxopentanoic acid (5 g) in acetic acid (40 ml) was added pyridine hydrobromide perbromide (12.3 g) and the mixture stirred at 20° C. for 18 hr, then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with water (100 ml), separated by hydrophobic frit and evaporated. The residue was taken up in ethanol (100 ml) and treated with concentrated sulphuric acid (1 ml) and heated at reflux for 18 h, then concentrated in vacuo to approx 30 ml. The mixture was diluted with water (250 ml) and extracted with diethyl ether (100 ml), dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (5.3 g).
Reaction SMILES: C(N1C=C(B2O[C:13](C)(C)[C:12](C)([CH3:17])[O:11]2)C=N1)C(C)C.Br[C:20]1[S:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1[CH:45]=[CH:44][C:42](N)=[CH:41][CH:40]=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[S:24][C:20]([C:41]4[CH:42]=[CH:44][CH:45]=[C:39]([O:11][CH:12]([CH3:17])[CH3:13])[CH:40]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Reactant: Nc1ccc(Br)cc1
Product: CC(C)Oc1cccc(-c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)c1

Procedure:
The title compound was prepared as described in Example 51A, substituting 2-(3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.04 (t, J=6.0 Hz, 1H), 8.49 (dd, J=7.0, 0.8 Hz, 1H), 8.19 (d, J=0.4 Hz, 1H), 7.89 (d, J=0.8 Hz, 1H), 7.86 (d, J=0.5 Hz, 1H), 7.75 (d, J=3.9 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J=3.9 Hz, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.48 (d, J=5.8 Hz, 2H), 4.13 (d, J=6.6 Hz, 2H), 3.09-2.83 (m, 4H), 2.47-2.40 (m, 1H), 2.14-1.96 (m, 1H), 1.88-1.69 (m, 1H), 1.69-1.54 (m, 1H), 1.37-1.14 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([CH2:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1)#N.[OH-:15].[K+].S(=O)(=O)(O)[OH:18]>>[CH2:13]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[N:5][CH:4]=[C:3]2[C:1]([OH:18])=[O:15])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: CCc1cccc2c(C#N)cnnc12
Agent: [K+]
Product: CCc1cccc2c(C(=O)O)cnnc12
Reaction time: 32 h

Procedure:
1.4 g of 53G was dissolved in 60 ml of 50% aqueous sulfuric acid and the mixture was stirred at 90°-100° C. for 32 hours. The mixture was cooled and made basic with 50% aqueous potassium hydroxide solution, then filtered. The filtrate was extracted with ether. The aqueous phase was acidified with 12 N hydrochloric acid and filtered. The resulting solid was dissolved in ethyl acetate, the solution was dried and stripped of solvent to give 53, as a solid, m.p.: 175°-176° C. (with decomposition).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[C:46]([O:49][CH2:50][CH3:51])(=[O:48])C>C(O)C.O>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:46]([O:49][CH2:50][CH3:51])=[O:48])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-cyanophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 657/659 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).