Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:12][S:13](C)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)(=[O:15])=[O:14]
Reactant: CCC(=O)c1ccnc(Br)c1
Reactant: CS(C)(=O)=O
Product: CCC(=O)c1ccnc(S(C)(=O)=O)c1

Procedure:
Alternatively, (1-(2-bromo-pyridin-4-yl)-propan-1-one could be converted to the corresponding methyl sulfone via the above procedure to afford 1-(2-methanesulfonyl-pyridin-4-yl)-propan-1-one. 1-(2-Methanesulfonyl-pyridin-4-yl)-propan-1-one can be converted to the title compound by methods described in example 82.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH3:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[CH2:19]([Al+]CC(C)C)C(C)C.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:17][CH3:19])[C@H:4]([CH3:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: CC(C)C[Al+]CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: COC(OC)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-carbobenzyloxy-L-alanine methyl ester (41.0 g, 0.71 mol) in 300 ml anhydrous toluene at -78° C., under N2, was added dropwise a toluene solution of diisobutyl-aluminum hydride (25% wt. % soln., 234 ml, 0.345 mol) over 0.5 hour. After the addition was complete the mixture was stirred 0.75 hour and quenched with the dropwise addition of 2N HCl (350 ml). The solution was warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 400 ml methanol and trimethylorthoformate (43 ml, 0.40 mol) and p-toluenesulfonic acid (0.723 g 3.8 mmol) was added. The mixture was stirred overnight and concentrated in vacuo to approximately 70% of the original volume. The residue was poured onto 800 ml of saturated NaHCO3. Ether and water were added. The aqueous layer was extracted with ether. The combined organic layers were washed with brine and dried (MgSO4) and concentrated in vacuo. Chromatography of the residue on HPLC using 30% ethyl acetate in hexanes as eluents provided the oily product N-carbobenzyloxy-L-alaninal dimethyl acetal.
Reaction SMILES: [CH:1]1[C:6]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[C:9]([CH:17]3[CH2:22][CH2:21][N:20](CCN4C(=O)NCC4)[CH2:19][CH2:18]3)=[CH:8]2)=[CH:5][CH:4]=[C:3]([F:31])[CH:2]=1.ClC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)C=C2.N1CCC(=O)CC1.ClC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)C=C2C1CCNCC=1>FC(F)(F)C(O)=O.C(O)(=O)C>[Cl:16][C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:7]([C:6]1[CH:5]=[CH:4][C:3]([F:31])=[CH:2][CH:1]=1)[CH:8]=[C:9]2[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Agent: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Agent: O=C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Fc1ccc(-n2cc(C3CCNCC3)c3cc(Cl)ccc32)cc1

Procedure:
Perregaard et al., J Med. Chem, 1992, 35, 1092-1101, disclosed a new method of preparing sertindole. This method comprises reaction of the intermediate 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of trifluoroacetic acid and acetic acid, reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon in the presence of K2CO3 and KI in methyl isobutyl ketone (MIBK). The 5-chloro-1-(4-fluorophenyl)indole was obtained from the corresponding 3-acetoxy-indole by NaBH4 reduction in methanol and subsequent elimination of H2O under acidic conditions. The 3-acetoxy-indole was prepared from the N-(4fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine following literature procedures.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:6]=[CH:7][C:8]=1[Cl:9]>C(O)(=O)C.[Pt]=O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COC(=O)c1ccncc1-c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.2 %

Procedure:
To a solution of the compound (18.1 g) obtained in step 1 in acetic acid (181 mL) was added platinum oxide (PtO2) (1.29 g), and the mixture was stirred overnight under a hydrogen atmosphere (5 atm) at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give methyl (3R*,4S*)-3-(3,4-dichlorophenyl)piperidine-4-carboxylate monohydrochloride (14.04 g, 76%) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[CH:22]1([C:28]2[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:28]2[CH:29]=[CH:30][C:31]([S:34][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=4[CH:21]=3)=[CH:32][CH:33]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][O:14][S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: OCC1COC(c2ccc(F)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(c3ccc(F)cc3)C2)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
2-(4-Fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran (21 g) is dissolved in 170 ml of pyridine whereupon 24.4 g of tosyl chloride is added below 4° C., and the resulting mixture is stirred at 4° C. for 1 hour and then at room temperature for 4 hours. The pyridine is then distilled off at room temperature under reduced pressure. Water is added to the residue and extracted with ethyl acetate. The extract is washed twice with dilute hydrochloric acid and once with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. To the residue are added n-hexane and isopropyl ether to give 32.7 g of 2-(4-fluorophenyl)-4-(tosyloxymethyl)tetrahydrofuran. This tosyl compound is recrystallized repeatedly from isopropanol to give cis-2-(4-fluorophenyl)-4-tosyloxymethyl)tetrahydrofuran as colorless needles, melting at 75°-76.5° C., and recrystallized from ethanol to give the trans-isomer as colorless needles, melting at 55°-57° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([N:20]2[CH2:36][CH2:35][C:23]3([N:27]=[C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[NH:25][C:24]3=[O:34])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:28]1([C:26]2[NH:25][C:24](=[O:34])[C:23]3([CH2:22][CH2:21][N:20]([S:17]([CH2:16][CH2:15][C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=4)(=[O:18])=[O:19])[CH2:36][CH2:35]3)[N:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Acetic anhydride (45 mg, 0.44 mmol) was added to a solution of 8-[2-(4-amino-phenyl)-ethanesulfonyl]-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (92 mg, 0.22 mmol) in CH2Cl2 (5 mL). Triethylamine (55 mg, 0.5 mmol) was then added on an ice bath, and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane, and the organic layer was then sequentially washed with water and saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by P-TLC to give N-{4-[2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-phenyl}-acetamide (55 mg, 54.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH3:29]B1OB(C)OB(C)O1.[OH-].[K+].C(O)(C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:15]2([CH2:14][O:13][CH2:12][C:4]3[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([CH3:29])[N:3]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:23][CH:24]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CN1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(COCC2(c3ccc(F)cc3)CCN(C)CC2)n1
Temperature: 100 °C
Yield: 39.6 %

Procedure:
2-chloro-6-(((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine (80 mg, 0.192 mmol), tetrakis(triphenylphsophine)palladium(O) (22.18 mg, 0.019 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (72.3 mg, 0.576 mmol) were combined in tetrahydrofuran (1.5 mL). The reaction was then treated with potassium hydroxide (0.392 ml, 0.392 mmol) and heated to 100° C. for 2 hours. After cooling, the solution was diluted with ethyl acetate (25 mL), washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified via preparatory HPLC to yield the desired product (30.23 mg, 0.076 mmol, 39.7%) as the TFA salt. 1H-NMR (CDCl3, 400 MHz) δ 10.02 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H). LC: Tr=1.920 min, HPLC Method 1. Mass spec.: 397.03 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccncc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 4-pyridinecarboxaldehyde to provide 45 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(C=Cc4ccncc4)c3C2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(N2Cc3cccc(CCc4ccncc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
2-(4-t-Butylphenyl)-7-(2-pyridin-4-yl-vinyl)-2,3-dihydro-isoindol-1-one (92 mg, Example 67) and 10% Pd/C (22 mg) were weighed into a flask. EtOH (7 mL) was added and the mixture was stirred under balloon pressure of H2 at RT for 8.5 h. Catalyst was removed by filtration and the filtrate was concentrated to give a white solid as crude product. The crude was purified by silica gel chromatography (25 g, 10-50% EtOAc/hexanes) to afford 2-(4-t-butyl-phenyl)-7-(2-pyridin-4-yl-ethyl)-2,3-dihydro-isoindol-1-one as a white solid. MS: (ES+) 371(M+H). Calc'd. for C25H26N2O—370.49.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.C(Cl)Cl>[CH2:18]([O:25][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)N1CCN(c2ncc(I)cn2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ncc(OCc3ccccc3)cn2)CC1
Temperature: 110 °C

Procedure:
To a stirred suspension of 5-iodo-2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine (25.0 g, 67.9 mmol), benzyl alcohol (125 mL), 1,10-phenanthroline (2.45 g, 20 mol %), and cesium carbonate was added copper (I) iodide (12.9 g, 67.9 mmol) and the reaction heated to 110° C. for 90 minutes then cooled to room temperature. DCM (250 mL) was then added and the insolubles filtered off through a pad of celite. The cake washed with DCM (250 mL) and the DCM filtrates washed with water. The aqueous phase was then back extracted with more DCM (500 mL), the combined DCM extracts washed with brine (500 mL), dried (MgSO4), filtered and concentrated in vacuo to a dark brown sludge. This was then purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to give 5-(benzyloxy)-2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine as an off white solid (14.2 g, 40.7 mmol, 60%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[CH3:39]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C:33]1[CH:34]=[C:35]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)[CH:36]=[CH:37][C:38]=1[CH3:39]
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cc1ccc(B(O)O)cc1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)c(C)c1
Yield: 71 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 3,4-dimethylphenylboronic acid (0.225 g; 1.5 mmol) in DME-water (2 mL) for 1 h. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.138 g (71%) of the title compound.
Reaction SMILES: [O:1]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH:6]([CH3:22])[C:5]2[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]=2[O:3]1.[H-].[Na+].Cl[P:38]1[O:45][C:44]2[C:46]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:47][C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:49][C:43]=2[CH:42]([CH3:58])[C:41]2[CH:59]=[C:60]([C:67]([CH3:70])([CH3:69])[CH3:68])[CH:61]=[C:62]([C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]=2[O:39]1>O1CCCC1>[C:14]([C:12]1[CH:11]=[C:10]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:8]2[O:9][P:2]([O:1][P:38]3[O:45][C:44]4[C:46]([C:54]([CH3:55])([CH3:56])[CH3:57])=[CH:47][C:48]([C:50]([CH3:53])([CH3:51])[CH3:52])=[CH:49][C:43]=4[CH:42]([CH3:58])[C:41]4[CH:59]=[C:60]([C:67]([CH3:68])([CH3:70])[CH3:69])[CH:61]=[C:62]([C:63]([CH3:66])([CH3:65])[CH3:64])[C:40]=4[O:39]3)[O:3][C:4]3[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:24]([C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:23][C:5]=3[CH:6]([CH3:22])[C:7]=2[CH:13]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[PH](=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Reactant: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(OP2Oc3c(cc(C(C)(C)C)cc3C(C)(C)C)C(C)c3cc(C(C)(C)C)cc(C(C)(C)C)c3O2)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 17.3 g (36 mmol) of the compound of Example 8 in 250 mL of dry tetrahydrofuran (THF) is added 1.0 g (41 mmol) of sodium hydride at 3° C. After the addition is complete, the reaction mixture is allowed to warm to room temperature. The reaction mixture is stirred for 14 hours at ambient temperature. To the reaction mixture is then added 14.8 g(29 mmol) of the compound of Example 7 at ambient temperature. After 48 hours, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography with 1% ethyl acetate/99% hexane to give the tide compound as a white solid melting at 281°-285° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14]C)[CH2:12]C)=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:22][CH2:21][CH2:20][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:14])[CH3:12])=[O:7])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Solvent: ClCCl
Product: CC(=O)NCCOc1cc(N)c(Cl)cc1C(=O)NCCN(C)C
Reaction time: 0.05 h
Yield: 54.1 %

Procedure:
To a solution of 4-amino-2-(2-aminoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide (780 mg, 2.4 mmoles) (prepared in Example 47) in methylene chloride was added acetic anhydride (245 mg, 2.4 mmoles) and the mixture stirred for 3 minutes. This was concentrated in vacuo and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was concentrated and the residue flash-chromatographed on silica using methylene chloride:methanol:ammonia (100:4:0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was recrystallized from methylene chloride-ether to give 445 mg of the title compound as a white solid, mp. 143°-145° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1NCCO1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 12.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and oxazolidin-2-one (435 mg), the title compound (260 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:26]#[N:27].[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[NH2:32].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N:15]4[CH2:20][CH2:19][CH:18]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:17][CH2:16]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:26]#[N:27])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1
Reactant: N#Cc1cnc2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1Cl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c([N+](=O)[O-])cc23)cc1Cl
Temperature: 105 °C
Yield: 60.9 %

Procedure:
A mixture of 0.5 g (1.45 mmol) of 4-chloro-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile, 0.38 g (1.6 mmol) of 3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]aniline and 0.17 g of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 105° C. for 1 hour. After cooling to room temperature, the mixture is stirred with 15 mL of saturated solution of sodium bicarbonate. The resulting solid is collected by filtration and washed with water. Some of the product dissolves in water, which is recovered by extracting the aqueous layer with solution of 95:5 methylene chloride/methanol. The organic layer is evaporated to provide crude product. The combined solids are purified by silica gel chromatography (gradient 95:5methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 0.52 g of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as an orange solid, mp 220-230° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.CS(O)(=O)=O.[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=O.[OH-].[Na+]>>[C:20]1([C:15]2[N:14]=[C:13]3[N:12]=[C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:19][C:18]3=[CH:17][CH:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1ccc(-c2ccccc2)nc1N
Agent: CS(=O)(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: COc1cccc(-c2nc3nc(-c4ccccc4)ccc3[nH]2)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Phosphorus pentachloride (0.5 g) was added to methanesulfonic acid (2 ml), and the mixture was stirred at 120° C. for 1 hour to make a solution. To the solution were added 2,3-diamino-6-phenylpyridine (Compound of Reference Example 113) (0.2 g) and 3-methoxybenzoic acid (0.17 g), and the mixture was stirred at 120° C. for 1 hour. The reaction mixture was poured onto ice, neutralized with 8 N sodium hydroxide solution and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 5-phenyl-2-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (0.18 g, 55%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:16]C(N)=O>O>[CH3:15][O:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:16][C:1](=[O:2])[CH2:4]2
Reactant: NC(N)=O
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Solvent: O
Product: COc1ccc2c(c1)CC(=O)NC2=O
Temperature: 25 °C

Procedure:
2-Carboxymethyl-4-methoxy-benzoic acid (946 mg, 4.5 mmole) and urea (629 mg, 10.4 mmole) is stirred and heated using an oil bath at 180° C. After one hour the mixture is cooled to room temperature and treated with water, collected by filtration, washed with water and dried to give a brown solid, 498 mg, (57%); mp 212-5° C., MS (ESI): m/z 192.1 (M+H).