Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([O:31]CC)=O)[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].[CH3:45][NH2:46].C(O)C>>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([NH:46][CH3:45])=[O:31])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)CC(C)C)cn1
Reactant: CN
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC)cn3[C@H](CO)CC(C)C)cn1
Yield: 80 %

Procedure:
A solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 119, 280 mg, 0.44 mmol) in 33 wt. % methylamine solution in absolute ethanol (4 mL, 32.13 mmol) was heated in the microwave at 80° C. for 30 min The reaction mixture was concentrated under reduced pressure. Purification via column chromatography to provide (silica, 95:5 methylene chloride/methanol) gave (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide as a light yellow solid (219.2 mg, 80%).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[O:29][C:28]([NH2:30])=[N:27][CH:26]=3)[CH:23]=2)[NH:18][N:17]=1.[C:31]([O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[O:29][C:28]([NH:30][C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:43][C:44]4[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=4)=[N:27][CH:26]=3)[CH:23]=2)[NH:18][N:17]=1
Reactant: Cc1n[nH]c2ccc(-c3cnc(N)o3)cc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cc1n[nH]c2ccc(-c3cnc(NC(=O)[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)o3)cc12

Procedure:
This intermediate was prepared by EDC-HOBt coupling of 5-(3-methyl-1H-indazol-5-yl)oxazol-2-amine with (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (purchased from Peptech (CAS No. 114873-07-3)) using a standard procedure such as described in Bioorg. Med. Chem. 14(2), 418-425; 2006) which is hereby incorporated by reference in its entirety as if specifically set forth herein.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])ccc1Nc1nccc(-c2cccnc2)n1
Yield: 61 %

Procedure:
2-Methyl-4-nitrophenyl-guanidine nitrate (26.3 g, 0.1 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (15 g, 0.08 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(2-methyl-4-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (15 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C(C)C)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone (example 15) and 3-chlorophenylboronic acid to afford the desired product as a colorless foam (65%). MS (ISP): 600.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][NH2:18]>C(O)C>[Br:1][C:2]1[C:7]([NH:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CN
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and methylamine in ethanol. ES-MS m/e (°/o): 271 (M{81Br}+H+, 95), 269 (M{79Br}+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])[CH2:27]P(OC)(OC)=O)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)C>[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])/[CH:27]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)CC(CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
In 10 mL of isopropanol (water content: 9,500 ppm) were dissolved 457 mg (2.6 mmol.) of 2,4-dichlorobenzaldehyde and 1.0 g (2.6 mmol.) of methyl 3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate to give an alcoholic solution. To the alcoholic solution was added 362 mg (2.3 mmol) of potassium carbonate, and the mixture was stirred for 3 hours at room temperature (22° C.). To the resulting reaction mixture was added 40 mL of ethyl acetate, and the mixture was stirred and washed with 20 mL of water. The washing was repeated twice. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered to give a filtrate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=95/5, volume ratio) to give 1.06 g (yield: 94%) of methyl (E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][C:2]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH3:3]
Reactant: CC(C)(C)OO
Reactant: CC(C)=CC(=O)C=C(C)C
Product: CC(C)(C)OOC(C)(C)CC(=O)CC(C)(C)OOC(C)(C)C

Procedure:
A mixture of 47.0 g. (0.34 mole) of phorone and 157 g (1.36 mole) of 78% t-butyl hydroperoxide was stirred with 34 g. of dry Amberlyst 15® sulfonic acid type ion exchange resin in a 500 ml flask equipped with a condenser and thermometer for forty-eight hours at 40° C. and one hour at 50° C. The ion exchange resin was separated by filtration and the product diluted with pentane. The pentane solution was washed with water, sodium bisulfite solution, 5% sodium hydroxide solution and water. After drying over anhydrous magnesium sulfate, the pentane was removed under reduced pressure. The recovered product weighed 74.2 g. (68.5% of the calculated amount). A GLC scan showed a large major peak for the expected product. In the infrared spectrum, small bands for hydroxyl and olefin were observed but the band in the 880 cm-1 region usually associated with t-butyl peroxy groups was strong. By active oxygen assay, the purity of the products was estimated at 83%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:5]1)(=O)C.[NH3:30]>CO>[C:19]([CH2:18][CH2:17][CH2:16][NH:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:14])(=[O:21])[NH2:30]
Reactant: COC(=O)CCCNC(=O)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C(C)=O
Reactant: N
Solvent: CO
Product: NC(=O)CCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 43 %

Procedure:
A sealed glass bomb containing methyl 4-{[1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-yl]carbonylamino}butanoate (95 mg, 0.239 mmol) in methanol with saturated ammonia (7 mL) was heated to 80° C. for 18 hours. The reaction mixture was condensed and he resulting solid was purified by HPLC to afford the title compound (35 mg, 43% yield). 1H NMR (DMSO-d6) δ 13.43 (br s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.87 (d, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 7.29 (s, 1H), 6.75 (br s, 1H), 3.75 (m, 2H), 2.09 (t, 2H), 1.73 (t, 2H); ES-MS (m/z) 341[M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[O:30]=[C:11]([N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17]1)[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:31]=[CH:32][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
4-Formyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (40 mg, 0.90 mmol) was dissolved in an acetone-water mixture (1:1, 0.9 mL) and cooled to 0° C. A mixture of sulphamic acid (26 mg, 0.27 mmol) and sodium chlorite (32 mg, 0.36 mmol) dissolved in minimum amount of water was then added. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. 5 mL of water was then added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 25 mg (61% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamic acid. LCMS Purity: 95.8%, 1H NMR (DMSO-d6): δ 13 (bs, 1H). 8.8 (m, 1H), 8.1-7.9 (m, 4H), 7.9-7.8 (m, 1H), 7.8-7.7 (m, 1H), 7.7 (m, 1H), 7.6-7.5 (m, 1H), 4.3-4.1 (m, 4H), 3.6-3.4 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:21])=[O:22])[CH3:34])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of [(R)-5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (example 2-2, method D, 2nd step) (400 mg, 0.85 mmol) in acetonitrile (15 mL) was added methyl iodide (182 mg, 1.28 mmol) and potassium carbonate (350 mg, 2.53 mmol). The reaction mixture was stirred at 70° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (365 mg, 89%) as a yellow oil. MS cald. for C23H27ClFNO5S 483, obsd. 484 (ESI+) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)c(Cl)c3)cc2sc1=O

Procedure:
7-(3-Chloro-4-fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3-chloro-4-fluoro-phenylboronic acid under conditions analogous to Example 7(a). MS ESI(+) m/e: 365.10 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(#N)C.[C:12](O)(=[O:14])[CH3:13]>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1ccccc1Br
Yield: 75 %

Procedure:
2-Bromo-1-acetylaminobenzene was synthesized in the usual manner from 2-bromoaniline. That is, 150 ml of acetonitrile was added to 25.0 g of 2-bromoaniline, then 15.1 ml of glacial acetic acid was added thereto, and the reaction mixture was heated under reflux for 2 hours. After bringing its temperature to room temperature, 300 ml of ethyl acetate was added thereto, and after the resulting mixture was washed with water twice, the solvent was distilled off, and recrystallization of the crude crystals from a hexane/ethyl acetate solvent mixture was carried out, to obtain 23.2 g (yield: 75%) of 2-bromo-1-acetylaminobenzene.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[C:31](=[O:40])[C:32]4[C:33](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]3=[O:35])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 70.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (17.0 g) and N-(6-bromohexyl)phthalimide (17.4 g) were reacted and treated in the same manner as in Preparation Example 150 to give 17.0 g of 4-amino-5-chloro-N-(1-(6-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)hexyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:62][C@H:63]([C:65](O)=[O:66])[CH3:64])=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:62][C@H:63]([C:65]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:66])[CH3:64])=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 71 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 71%. [α]D =+7.4° (c=0.82, tetrahydrofuran).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][C:3]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24].C(OCC)(=O)C>CN(C)C=O>[CH3:24][O:23][CH:22]([O:25][CH3:26])[CH2:21][N:9]1[C:10]2[C:5](=[N:4][C:3]([CH3:13])=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: COC(CBr)OC
Reactant: Cc1nc2ccc(=O)[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(Cn1c(=O)ccc2nc(C)c(F)cc21)OC
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 0.74 g of 7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one in 5 mL of N,N-dimethylformamide, 2.0 g of cesium carbonate and 0.84 g of 2-bromo-1,1-dimethoxyethane were added, the temperature was increased to 90 to 100° C., and the mixture was stirred for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, thereto was added ethyl acetate, the insoluble substance was filtered off, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.69 g of 1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH3:26].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN(C)CCCCN
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCCN(C)C)c(C(=O)O)c1Cl
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of Example 389B (133 mg, 0.4 mmol), 4-(N,N-dimethylamino)butylamine (346 mg, 3.0 mmol), acetonitrile (3 mL), and triethylamine (0.3 mL, 1.9 mmol) was sealed in a vial and shaken at to 80° C. for 72 hours. The mixture was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 454 (M+H)+; (ESI(−)) m/e 452 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.43 (d, 1H), 7.36 (m, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 6.61 (t, 1H), 5.78 (br s, 1H), 3.31 (br s, 2H), 3.23 (m, 2H), 3.04 (m, 2H), 2.76 (s, 6H), 2.59 (q, 2H), 1.86 (m, 2H), 1.66 (m, 2H), 1.09 (t, 3H).
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1SC.[NH2:17][NH2:18]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1[NH:17][NH2:18]
Reactant: NN
Reactant: CSC1NCCCN1CCO
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)C
Solvent: CCO
Product: NNC1NCCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-hydroxyethyl)-2-methylthio-3,4,5,6-tetrahydropyrimidine mesylate (87.2 g) is suspended in ethyl alcohol (150 ml) and treated with anhydrous hydrazine (22 mL). The mixture becomes clear within a few minutes. It is stirred at room temperature overnight and then diluted with t-butyl methyl ether (2 liters). The solution is kept in the freezer at -20° C. until the solid separates, filters and dries. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 68.12 g of 1-(2-hydroxyethyl)- 2-hydrazino-3,4,5,6-tetrahydropyrimidine mesylate, melting point 82.2°-84.4° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>>[F:26][C:24]1[CH:23]=[CH:22][C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)ccc1O
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)ccc1O
Yield: 62.3 %

Procedure:
The product is prepared according to the procedure described in Stage 1 of Example 2, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of 2-amino-4-fluorophenol in place of the 2,4-difluoroaniline. 795 mg of N-(5-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24].C(=O)(O)[O-].[Na+:30].O>O1CCCC1>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([O-:25])=[O:24].[Na+:30]
Reactant: O=C(O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid (34.9 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added sodium bicarbonate (8.4 mg, 0.10 mmol) and water (2 mL). The reaction mixture was stirred at room temperature for 1 hour then freeze dried, to give sodium 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate.