Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C1OCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Temperature: 70 °C

Procedure:
A mixture of 6-hydroxyisochroman-1-one (332 mg), methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (284 mg), cesium carbonate (1.28 g) and DMF (8 mL) was heated at 70° C. for 7 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel. The product with the molecular weight of 248.28 (C14H16O4) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: BrCCCCO[CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:15][CH2:16][CH2:7][CH2:8][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[CH2:7][CH2:16]2
Reactant: O=C1Nc2ccccc2CC1OCCCCBr
Reactant: COc1ccccc1S
Product: COc1ccccc1SCCCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 2-methoxy-thiophenol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH:34]5[CH2:38][CH2:37][O:36][CH2:35]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NC1CCOC1
Product: O=C(NC1CCOC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 119.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-aminotetrahydrofuran (available from Aldrich Chemical Company, Inc.; 54 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(tetrahydro-furan-3-ylcarbamoyl)-biphenyl-2-carboxylic acid (135 mg, 121%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 8.62 (d, J=6.5 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 4.43-4.54 (m, 1H), 3.84-3.92 (m, 2H), 3.69-3.77 (m, 1H), 3.61 (dd, J=8.9, 4.4 Hz, 1H), 2.12-2.22 (m, 1H), 1.90-2.00 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1ccccc1Cl
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3Cl)nc2n(CCC)c1=O
Yield: 75 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.00 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.67 g (14.6 mmol) of 2-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.72 g (yield 82%) of Compound 41 as white needles.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH3:22])[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].CN(C)C=O.C(N(CC)CC)C.Cl.[F:50][C:51]1([F:57])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>O1CCCC1.O>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([NH:15][C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:54]4[CH2:55][CH2:56][C:51]([F:57])([F:50])[CH2:52][CH2:53]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:36])([CH3:33])[CH3:32])#[N:35]
Reactant: FC1(F)CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CN3CCC(F)(F)CC3)sc2n1
Temperature: 60 °C
Reaction time: 7 h
Yield: 47.1 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}amino)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (150 mg, 288 μmol) produced in Example D32(i) in tetrahydrofuran (4 mL)/N,N-dimethylformamide (0.5 mL) were added triethylamine (180 μL, 1.30 mmol) and 4,4-difluoropiperidine hydrochloride (68 mg, 432 μmol), and the mixture was stirred at 60° C. for 7 hr. To the reaction mixture was added water (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (82 mg, 47%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.[Na+].[I-]>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
200 g (1.16 mol) of 4-bromophenol was dissolved in 2.1 L acetone under argon. Then 320 g (2.31 mol) K2CO3 and 3.465 g (23.1 mmol) NaI were added. The mixture was stirred at room temperature and 292.7 g (2.31 mol) of benzyl chloride was added during 1 h. Then the mixture was boiled during 48 h. The acetone (ca. 500 mL) was partially removed on the rotary evaporator. 1.2 L 10% aq. Na2CO3 was added to the residue. After extraction with ethyl acetate (1×1 L+2×500 mL) the organic phase was washed with 1 L of a half-saturated NaCl solution. After drying over Na2SO4 and concentrating, the main part of the benzyl chloride was removed. 400 mL of pentane was added to the residue. The crystallisation began during stirring at 0° C. The crystals were separated and washed with 2×150 mL pentane and dried during 2 h at 15 mbar (40 C° bath temperature) and 2 h under high vacuum at room temperature to yield 230 g (75%) 4-benzyloxybromobenzene.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[C:18]([O:19][C:20]2([CH:26]([N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([OH:29])=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:17]([F:45])[C:16]([F:46])=[CH:15][CH:14]=1>CN(C=O)C.O>[CH2:38]([N:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:26]1[C:20]2([CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[O:19][C:18]2[C:17]([F:45])=[C:16]([F:46])[CH:15]=[CH:14][C:13]=2[NH:12][C:27]1=[O:29])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(F)c(F)c1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c(F)c2OC2(CCOCC2)C1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
H2O (70.5 mg, 460 μmol, Eq: 1.2) and EDCI (88.2 mg, 460 μmol, Eq: 1.2) were added to a solution of [4-(6-amino-2,3-difluoro-phenoxy)-tetrahydro-pyran-4-yl]-dibenzylamino-acetic acid (185 mg, 383 μmol, Eq: 1.00) in DMF (5 mL). The mixture was stirred at RT overnight, diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 3-(dibenzylamino)-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one (102 mg, 57% yield). MS m/z 465.0 (MH+)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:17]([NH:19][O:20][CH3:21])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:17]([NH:19][O:20][CH3:21])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Yield: 91.5 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-N-methoxy-4-methyl-benzamide (1.80 g, 10 mmol) and DIEA (1.9 mL) in THF (80 mL) were stirred at room temperature for overnight. The solvent was removed in vacuo and the product (3.33 g, 92%) was obtained after purification by silica gel column chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:14])[CH:3]=1.C(N(CC)CCNC(C1C=C(I)C=C2C=1N=CC=C2[F:41])=O)C>>[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][NH:15][C:13]([C:4]1[CH:3]=[C:2]([F:41])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=1)=[O:14])[CH3:20]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c2cc(I)ccc2n1
Reactant: CCN(CC)CCNC(=O)c1cc(I)cc2c(F)ccnc12
Product: CCN(CC)CCNC(=O)c1cc(F)c2cc(I)ccc2n1
Yield: 48 %

Procedure:
This compound was prepared, starting from compound 105 (1.00 g, 2.32 mmol), according to the procedure developed for compound 102. Reaction time at 200° C.: 2 h, reaction time at 140° C.: 5 h; the purification was performed using column chromagraphie (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 106 (458 mg, 1.10 mmol) as a yellow solid. Yield 48%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.42; mp 58-60° C.; IR (KBr) ν 1342, 1486, 1518, 1555, 1681, 2760, 2966, 3385 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.06 (t, 6H, J=7.1 Hz), 2.56 (q, 4H, J=7.1 Hz), 2.69 (t, 2H, J=6.1 Hz), 3.54 (q, 2H, J=6.1 Hz), 7.76 (dd, 1H, 5JH-F=1.2 Hz, J=8.9 Hz), 7.96 (m, 2H), 8.42 (d, 1H, J=1.7 Hz), 8.50 (m, 1H); ESI-MS m/z 415.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:19]=[O:20])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Cl
Reaction time: 3 h

Procedure:
Under nitrogen, a solution of 1.6 g of 2,4-dichloropyridine in 5 mL dry tetrahydrofuran (THF) was added to a solution of 6 mL of lithium diisopropyl amide in 25 mL of THF at −70° C., followed by stirring at this temperature for 3 hours. Then 1 mL of dry N,N-dimethylformamide was added at −70° C. followed by stirring at this temperature for 1 hour. Then 25 mL of saturated ammonium chloride solution was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 25 mL of water and extracted with ethyl acetate (2×). The combine organic phases were distilled under vacuum to give solids that were dissolved in 5 mL of methylene chloride and filtered through silica gel, eluting with 100% methylene chloride. Removal of the solvent under vacuum provided the title intermediate as a solid. 1H NMR (CDCl3; 300 MHz) δ 7.41 (d, 1H, J is 5.3 Hz), 8.42 (d, 1H, J is 5.2 Hz), 10.5 (s, 1H).
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C=CC=CC=1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
In a 500-ml four-necked flask were placed 22.4 g (0.10 mole) of 1,3-diphenylpropanedione, 20.0 g (0.13 mole) of p-nitrophenylhydrazine, and 200.7 g of toluene. The mixture was then heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by reslurrying by adding 300 ml of methanol. Thereafter, the residue was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 26.0 g of 1-(p-nitrophenyl)-3,5-diphenylpyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:14]2[C:13](=[O:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:29][CH2:28]1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Reactant: ClCC1CC1
Product: COc1ccc(-c2cc(=O)n(CC3CC3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 93 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 93.0%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=[O:18])([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:2][CH:3]=[C:4]([O:18][C:15]2[CH:4]=[CH:3][CH:2]=[CH:11][CH:6]=2)[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
Methyl 5-chloro-2-nitrobenzoate (1) is reacted with an appropriately-substituted phenol (2) and base such as potassium carbonate in a solvent such as NMP to form the corresponding phenoxy-2-nitro-benzoic acid methyl ester (3). Compound (3) is hydrolyzed upon treatment with basic solution such as NaOH in water/MeOH to provide benzoic acid (4). Benzoic acid (4) is treated with thionyl chloride in solvent such as DMF to provide an intermediate acid chloride, which upon treatment with NH4OH in solvent such as THF provides benzamide (5). The nitro-benzamide (5) can be hydrogenated in solvent such as EtOH to provide amino-benzamide (6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)=[N:9][N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.ClCCl>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH3:32])=[C:15]([NH2:17])[N:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:9]=2)[N:12]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In pyridine (600 ml), 31.75 g (86.20 mmol) of the compound from Example 11A were introduced under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off on a frit, after which it was washed with ethanol and ethyl acetate. Subsequently the residue was again stirred with diethyl ether, isolated by filtration with suction and then dried under a high vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]1([CH3:30])[C:23]2([CH3:29])[C:24]([O:26][C:27](=O)[CH:20]1[CH2:21][CH2:22]2)=[O:25]>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:27](=[O:26])[CH:20]3[C:19]([CH3:18])([CH3:30])[C:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]2=[O:25])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Product: CC12CCC(C(=O)N(CCCCN3CCN(c4ncccn4)CC3)C1=O)C2(C)C
Yield: 17 %

Procedure:
The title compound was prepared from 2.47 g (10.4 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.89 g (10.3 mmol) of dl-camphoric anhydride, substantially according to the procedure of Example 1. This afforded 0.7 g of product, mp 94°-97° C. (17% yield).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH:12]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4cccnc4)cc3)c2cc1C#N
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4cccnc4)cc3)c2cc1C#N
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.27 ml) was added dropwise to a stirred solution of N-(3-pyridyl)-2-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]acetamide (0.1 g) in DMF (2 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.026 ml) in DMF (0.5 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.04 g); 1H NMR: (CDCl3) 3.34 (s, 3H), 3.52 (s, 2H), 4.08 (s, 3H), 6.51 (d, 1H), 7.07 (d, 2H), 7.18 (d, 2H), 7.42 (m, 1H), 7.53 (br s, 2H), 8.5 (br s, 1H), 8.65 (br s, 1), 8.67 (d, 1H), 8.69 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=[C:40]2C(C(N3CCNCC3)=C[CH:38]=[N:39]2)=CC=1.C(N(C(C)C)CC)(C)C.CN(C)C1C=CC(N=C=O)=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:39]([CH3:40])[CH3:38])=[CH:25][CH:26]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: CN(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol), diisopropyl(ethyl)amine (209 mg, 1.62 mmol), and 4-(dimethylamino)phenyl isocyanate (157 mg, 0.97 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [N+:1]([N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:5]([C:13]([OH:15])=O)[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])([O-:3])=[O:2].ClC(OCC(C)C)=O.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.C(N(CC)CC)C>[N+:1]([N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:5]([C:13]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH3:31])=[O:15])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])([O-:3])=[O:2]
Reactant: CCCCNC
Reactant: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(C)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]

Procedure:
A 3.2 gram amount of NG -nitro-N2 -(tert-butyloxycarbonyl)-L-arginine was dissolved in a mixture of 40 ml of dry tetrahydrofuran and 1.4 ml of triethylamine. To the solution was added 1.4 ml of isobutyl chloroformate with stirring and cooling in an ice-salt bath. After additional stirring for 15 minutes, 0.87 gram of N-methyl-n-butylamine was added to the mixture. Then the reaction mixture was stirred continuously for 40 minutes at room temperature. The solvent was removed by distillation under reduced pressure, below 40° C. The residue was extracted with 100 ml of ethyl acetate and the extract was washed successively with a 10% aqueous citric acid solution, saturated sodium chloride solution, saturated aqueous sodium bicarbonate solution, and finally with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give NG -nitro-N2 -(tert-butyloxy-carbonyl)-N-(n-butyl)-N-methyl-L-argininamide. This material was added to ethyl acetate containing 10% dry HCl and allowed to stand for 2 hours, and NG -nitro-N-(n-butyl)-N-methyl-L-argininamide hydrochloride was precipitated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2cccc(OCC(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of methyl 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetate (75 mg, 0.19 mmol) in EtOH (4.0 mL) and H2O (4.0 mL) was added 3M aqueous NaOH (0.30 mL, 1.0 mmol). The reaction mixture was left to stir at rt overnight. Then, the mixture was acidified with 1M HCl aqueous to pH=2. Vacuum filtration afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=4.80 (s, 2H), 6.93 (dd, J=7.7, 2.1 Hz, 1H), 7.25-7.29 (m, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.55-7.62 (m, 1H), 8.15 (dd, J=18.4, 7.6 Hz, 2H), 8.31 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.3 Hz, 1H), 13.06 (br. s., 1H). MS (ES+): m/z=378.07 (100) [MH+]. HPLC: tR=3.50 min (ZQ3, polar—5 min).