Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl.Cl[CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>C(N(CC)CC)C>[CH3:1][N:2]([CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: ClCCN1CCOCC1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(CCN1CCOCC1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 51.7 %

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745), 29 mg 4-(2-chloroethyl)morpholine hydrochloride and 21 μL triethylamine were reacted in the same manner as in Example 746, to give 60 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methyl-(2-morpholin-4-yl-ethyl)amide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 45 mg of the title compound as yellow crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:27]#[N:28])=[N:21][C:22]([Cl:26])=[CH:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[Cl:26][C:22]1[CH:23]=[C:24]([CH3:25])[C:19]2[C:20](=[C:27]([NH2:28])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: Cc1cc(Cl)nc(C#N)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(Cl)nc2c(N)nc3ccccc3c12
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-chloro-4-methylpicolinonitrile (from step 2) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 3-chloro-1-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (dmso-d6): δ 8.44 (d, 1H), 7.83 (s, 1H), 7.50-7.58 (m, 2H), 7.02 (bs, 2H), 2.98 (s, 3H). LRMS [M+H]=244.1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[NH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:18])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)CCCN2
Reactant: CO
Product: COC(=O)c1ccc2c(c1)CCCN2
Product: Cl

Procedure:
0.93 g of 1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 100 ml of methanol are placed in a 500 ml round-bottomed flask under a nitrogen atmosphere. 0.46 ml of thionyl chloride is added at 0° C. and then the reaction mixture is stirred at reflux for three hours. After evaporating the solvent, the residue is triturated in ethyl ether and then the solid obtained is filtered off and dried under vacuum. 1.13 g of methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate hydrochloride are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[NH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([NH:18][CH:19]2[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCC(NC(=O)C=Cc2ccc(OC(C)=O)c(OC)c2)CC1
Yield: 60.2 %

Procedure:
Using 2.5 g of 4-acetoxy-3-methoxycinnamoyl chloride, 3.7 g of ethyl 4-amino-1-cyclohexanecarboxylate described in the literature [V. Skaric, M. Kovacevic, and D. Skaric, J. Chem. Soc. Perkin I, 1199-1201 (1976)], and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 2.3 g of ethyl 4-(4-acetoxy-3-methoxycinnamamido)-1-cyclohexanecarboxylate (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([O:21][CH2:22][CH2:23]O)[CH2:17][CH2:18][S:19][CH3:20])=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CSOC(I)=O>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([CH:16]([CH2:17][CH2:18][S:19][CH3:20])[O:21][CH2:22][CH2:23]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C(CCSC)OCCO)[nH]c(=O)c1OCc1ccccc1
Agent: CSOC(=O)I
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Reaction time: 20 h
Yield: 52.4 %

Procedure:
To a solution of intermediate 20, ethyl 5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (527 mg, 1.25 mmol) and Et3N (505 mg, 5 mmol) dissolved in 10 mL of CH2Cl2 was added a solution of CH3SO2CI (288 mg, 2.5 mmol) dissolved in 2 mL of CH2Cl2. This was stirred for 20 hrs then concentrated. The crude product was purified by chromatography on silica gel, using 10:1 CH2Cl2:ether as eluent, to give the title compound 265 mg (52% yield). (500 MHz, CDCl3) δ ppm: 7.31-7.55 (5 H, m) 5.30 (2 H, s) 4.75 (1 H, dd, J=3.66 Hz) 4.32-4.40 (2 H, q, J=7.17 Hz) 4.13-4.30 (2 H, m) 3.75-3.97 (2 H, m) 2.20-2.84 (4 H, m) 2.06 (3 H, s)1.32 (3 H, t, J=7.17 Hz); LC/MS m/z 405 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.C(O[BH-](O[C:42](=[O:44])[CH3:43])OC(=O)C)(=O)C.[Na+].[CH2:46]1[CH2:50]OC[CH2:47]1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([CH:47]4[CH2:43][CH2:42][O:44][CH2:50][CH2:46]4)[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CCOCC3)C2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 24 %

Procedure:
To a solution of [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (408 mg, 0.92 mmol) in THF (4 mL) was added under an atmosphere of nitrogen tetrahydro-4H-pyran-4-one (25 mg, 0.25 mmol). After stirring for 15 min. at ambient temperature sodium triacetoxyborohydride (252 mg, 1.19 mmol) was added and stirred continued for 4 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with an aqeuous solution of sodium carbonate (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layers were dried of sodium sulfate. Concentration and purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 80:20) afforded the title compound (115 mg, 24%) as a light yellow oil. MS m/e: 530.3 [M]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1)(O)(=O)=O>>[CH3:26][N:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Product: CN(c1ccc(O)cc1)c1cnc2cc(Cl)c(Cl)cc2n1

Procedure:
2,6,7-Trichloroquinoxaline was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenol. Proton magnetic resonance spectrum (d6 -acetone; δ in ppm): 8.25 (1H, s, quinoxaline hetero-ring proton); 8.0 (1H, s, quinoxaline benzo-ring proton); 7.9 (1H, s, quinoxaline benzo-ring proton); 7.15 (4H, m, phenoxy protons; 3.55 (3H, s, N-CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1.[C:24]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(=[O:26])[CH3:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:31][CH2:32][CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH2:29]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.22 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid and 0.11 g of 3-acetamidopyrrolidine are added to 12 ml of pyridine, and added with 0.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20 ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction. (next reaction: Example 5)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH:9]1[C:15]([OH:17])=O)=O)(C)(C)C.C([N:20]([CH2:23][CH3:24])CC)C.ClC(OCC(C)C)=O.Cl[C:34]1[CH:35]=[C:36]([CH:41]=C[CH:43]=1)[C:37]([NH:39]O)=[NH:38]>C1COCC1.CN(C=O)C>[CH3:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH:9]1[C:15]1[O:17][N:39]=[C:37]([C:36]2[CH:41]=[C:24]([CH:43]=[CH:34][CH:35]=2)[C:23]#[N:20])[N:38]=1
Reactant: CC1CCCN(C(=O)OC(C)(C)C)C1C(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1CCCNC1c1nc(-c2cccc(C#N)c2)no1
Temperature: 135 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
2-[3-(3-cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 14.7%) was obtained as described in Example 25 from 3-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (672 mg, 2.765 mmol) with triethylamine (1.1 g, 11 mmol) in THF (8 mL) with isobutyl chloroformate (377.6 mg, 2.765 mmol). After 30 minutes, 3-chloro-N-hydroxy-benzamidine (445 mg, 2.765 mmol) in DMF (5 mL) was added and then the reaction mixture was heated to 135° C. for 3 h. The product was purified by column chromatography with 5% ethyl acetate in hexanes. 3-[5-(3-methyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (85 mg, 77.8%) was obtained as described in Example 25 from 2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.407 mmol) with trifluoroacetic acid (0.5 mL) and dichloromethane (4 mL) at room temperature for 2 h.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[F:13].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:13])=[C:6]([F:12])[C:7]2[N:11]=[C:18]([C:17]3[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:24])[NH:10][C:8]=2[CH:9]=1)=[O:14]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(N)c(N)c(F)c1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: COC(=O)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,5-diamino-2,3-difluorobenzoic acid methyl ester (404 mg, 2.0 mmol) and 2,6-dichlorobenzaldehyde in DMSO (15 mL) was added Yb(OTf)3 (248 mg, 20%) and the solution was stirred at ambient temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid methyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[C:19]([C:21]#[N:22])C=[CH:17][C:16]=2O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-:27].[Na+].OO.[CH3:31][OH:32].C(Cl)(Cl)Cl>C(O)C.CS(C)=O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:24])[C:15]2[CH:16]=[CH:17][C:31]([OH:32])=[C:19]([C:21]([NH2:22])=[O:27])[CH:20]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: CO
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
N-(3,5-bis-trifluoromethyl-phenyl)-5-cyano-2-hydroxy-benzamide (150 mg, 0.4 mmol) obtained in step 1 was dissolved in ethanol (1.74 ml) and DMSO (0.8 ml). 1 M NaOH (0.33 ml) was added thereto, to which 30% H2O2 (0.33 ml) was added. The reaction mixture was stirred overnight at room temperature. The solution was eliminated under reduced pressure. The residue proceeded to column chromatography (5% MeOH—CHCl3) to give 149 mg of the target compound (yield: 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=[CH:3]1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19]O)=[NH:18])=[N:15][CH:16]=1.O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:19]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[O:8][N:18]=2)=[N:15][CH:16]=1
Reactant: N=C(NO)c1ccc(Cl)cn1
Reactant: Cn1cncc1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1cncc1-c1nc(-c2ccc(Cl)cn2)no1
Temperature: 25 °C
Yield: 4.6 %

Procedure:
A mixture of 3-methyl-3H-imidazole-4-carbonyl chloride (91 mg, 0.5 mmol), 5-chloro-N-hydroxy-pyridine-2-carboxamidine (85.8 mg, 0.5 mmol) in pyridine (5 ml) was refluxed for 4 h and then cooled to room temperature. To the solution was added water (20 ml) and the product precipitated from the solution. The solid was collected by filtration and washed with water, dried to give 6 mg (5%) of the title compound. 1H NMR (CDCl3): 8.78 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.87 (dd, J=2.7 Hz, J=8.7 Hz, 1H), 7.70 (s, 1H), 4.14 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([OH:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(C(C)=O)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(C(C)=O)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
Ethyl 5-acetylsalicylate (211 mg), 4-chloro-6,7-dimethoxyquinoline (111 mg), and 4-dimethylaminopyridine (183 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (19 mg, yield 5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[NH:23][C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH:31]([CH3:35])[C:32](=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[N:23]([CH:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(C)(C)C4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)N(C(C)C(C)=O)C(C)(C)C4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A mixture of 21.3 parts of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4-imidazolidinedione, 7.5 parts of 3-chloro-2-butanone, 6.0 parts of potassium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at 100° C. After cooling, the reaction mixture was diluted with 700 parts of water. The crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. After trituration of the residue in methanol, the product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 7.77 parts (30.9%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-1-(1-methyl-2-oxopropyl)-2,4-imidazolidinedione; mp. 225.9° C. (intermediate 20).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]([Cl:19])([Cl:18])=[CH2:17].Cl>C(Cl)Cl>[Cl:18][C:16]([Cl:19])=[CH:17][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2Cl2 (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (0.64 g, 4.76 mmol) in CH2Cl2 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: 1H-NMR (CDCl3, 300 MHz) δ 8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); Rf=0.51 (4:1 Hex:EtOAc).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#N)=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C(C#N)=C2C(C(=O)C(C(O)=O)=CN2C2CC2)=CC=1F.C(C1C(F)=C(C=C(F)C=1F)C(F)=O)#N.FC1C=C(C)C=C(C)C=1>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[CH3:4]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Agent: Cc1cc(C)cc(F)c1
Agent: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Product: Cc1cc(F)c(Cl)c(C)c1Cl

Procedure:
An alternative process for the preparation of the intermediate compound 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride, which serves as a starting material for the preparation of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (EP-A-0 276 700) and which can converted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride, starts from 5-fluoro-1,3-xylene: 5-fluoro-1,3-xylene is dichlorinated in the nucleus under ionic conditions in the presence of a catalyst to give 2,4-dichloro-5-fluoro-1,3-dimethylbenzene and this is then chlorinated under free-radical conditions in the side chains to give 2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene. This is hydrolysed via 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid to give 2,4-dichloro-5-fluoro-3-formyl-benzoic acid and then reacted to give 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid. By treatment with thionyl chloride, 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride is obtained, which can additionally be reacted by means of a chlorine/fluorine exchange to give 3-cyano-2,4,5-trifluoro-benzoyl fluoride. ##STR4##
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 5,6-dichloropyrimidine-2,4-diamine (68.8 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (22 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.41 (m, 3 H), 2.70-2.82 (m, 2 H), 3.00-3.15 (m, 3 H), 3.69-3.93 (m, 10 H), 5.55-5.67 (m, 2H), 5.79-5.89 (m, 1 H), 5.89-5.96 (m, 2 H), 6.11-6.22 (m, 1 H), 6.47-6.57 (m, 1 H), 7.49-7.59 (m, 1 H), 7.75-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H23ClN8O, 403. found 403.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](CCN)=[CH:7][CH:6]=1.CC(C)=O.N1C=CC=CC=1.C(OC1C=CC(Cl)=CC=1C(Cl)=O)C>O1CCOCC1>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CCN)cc1
Agent: CCOc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1

Procedure:
10.5 g of 4-(2-aminoethyl)-benzoic acid methyl ester-hydrochloride were suspended in 40 ml of dioxane and 20 ml of acetone and the suspension was combined with 8 ml of pyridine. To this suspension, a solution of 10 g of 2-ethoxy-5-chloro-benzoyl chloride in a small amount of acetone was added dropwise, while stirring, and the whole was heated for 2 hours under reflux. After cooling, the mixture was concentrated under reduced pressure, combined with ice-water, filtered with suction, stirred with dilute hydrochloric acid and with a NaHCO3 solution and the resulting product was again filtered off with suction and recrystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid methyl ester obtained was found to melt at 110° C.