Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:23][N:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])[CH:2]=1
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccs3)ns2)CC1
Yield: 36.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 109 mg (37.1%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCn1ccnc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ccnc(-c2ccc(Cl)cc2)c1=O
Yield: 47.6 %

Procedure:
To 200 mg (0.98 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 57 mg (0.05 mM) of palladium tetrakis triphenylphosphine in 4 ml of toluene were added, under nitrogen, 231.0 mg (1.48 mM) of 4-chlorophenylboronic acid and 2.9 ml of 2M sodium carbonate aqueous solution The mixture was stirred for 3 h at reflux under nitrogen atmosphere, and then at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug, eluting with dichloromethane, which afforded 110 mg of 3-(4-chlorophenyl)-1-ethylpyrazin-2(1H)-one as a solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].F[C:16]1[CH:17]=[C:18](C)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].[CH2:26]1COCC1>>[CH2:13]([O:12][C:10]([C:5]1[CH:6]=[N:7][N:8]([CH3:9])[C:4]=1[NH:3][C:20]1[CH:19]=[CH:18][C:17]([CH3:26])=[CH:16][C:21]=1[N+:22]([O-:24])=[O:23])=[O:11])[CH3:14]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnn(C)c1Nc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.28 g, 180 mmol) was added portionwise to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (21.8 g, 148 mmol) in anhydrous THF at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 h then a solution of 3-fluoro-4-nitrotoluene (20 g, 129 mmol) in anhydrous THF (50 ml) was added dropwise. The resultant deep purple solution was stirred at room temperature for 18 h then poured into ice-cold 1N hydrochloric acid. The resulting mixture was extracted with dichloromethane (200 ml×2), and the combined organic extracts were washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 60% pet ether:40% EtOAc) to yield the title compound (28.00 g, 61%).
Reaction SMILES: C[CH:2]([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].[C:9]1([CH:15]2[NH:20][CH2:19][CH2:18][N:17]3[CH:21]=[CH:22][CH:23]=[C:16]23)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(CC)CC.C(Cl)(Cl)Cl.[C:35](OCC)(=[O:37])C>C(Cl)Cl>[CH3:35][O:37][C:6](=[O:7])[CH2:2][C:3](=[O:4])[N:20]1[CH2:19][CH2:18][N:17]2[CH:21]=[CH:22][CH:23]=[C:16]2[CH:15]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: c1ccc(C2NCCn3cccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(=O)N1CCn2cccc2C1c1ccccc1
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of (852 μl, 7.9 mmol) of methyl-malonyl chloride in DCM (5 ml) was added dropwise, with vigorous stirring and while cooling (ice-bath), to a solution of (1.5 g, 7.6 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A2) and (1.27 ml, 9.1 mmol) of NEt3 in DCM (35 ml). Stirring was then carried out for 60 min at RT. The mixture was then washed with water and brine, and the organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (chloroform/ethyl acetate 10:1) yielded 1.26 g (4.2 mmol, 55%) of 3-oxo-3-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propanoic acid methyl ester.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[C:9]([O:16][CH3:17])=[CH:10][C:11]([F:15])=[C:12]([CH:14]=1)[NH2:13].N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[C:9]([O:16][CH3:17])=[CH:10][C:11]([F:15])=[C:12]([NH:13][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:14]=1
Reactant: COc1cc(F)c(N)cc1Br
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(Br)c(OC)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.5 %

Procedure:
At 0° C., ethansulfonylchloride (1.4 g, 10.9 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-4-methoxyaniline (3.5 g, 24.0 mmol) in pyridine (1.3 g, 16.4 mmol) and dry CH2Cl2 (20 mL). After stirring at room temperature for 10 h, CH2Cl2 extractive work up and purification by silica gel chromatography (PE:EA=10:0 to 3:1) gave the title compound (2.5 g, 73.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.4 Hz, 1H), 6.73 (d, J=11.6 Hz, 1H), 6.27 (s, 1H), 3.89 (s, 3H), 3.10 (q, J=7.6 Hz, 2H), 1.40 (t, J=7.6 Hz, 3H). LCMS: 334.0 (M+Na)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: C1CCCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CN2CCCCCC2)c1
Yield: 70.1 %

Procedure:
To a solution of 3-nitrobenzyl bromide (10.5 g, 48.7 mmol) in methylene chloride is added azepane (5.5 mL, 48.7 mmol) and 20.0 mL (146.1 mmol) of triethylamine, and the reaction solution is heated at 60□C under N2 for 20 minutes. After evaporating to dryness, the resulting brown residue is dissolved in methylene chloride and washed twice with saturated Na2CO3 solution, and once with brine solution. After drying over Mg2SO4, the organic solution is filtered and concentrated to give 8.0 g (70.1% yield) of brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1COC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 79.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methoxyphenyl)methanol (71 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (123 mg, yield 73%).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])C.O.Cl>C1COCC1.CO.O>[C:13]1([C:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
LiOH (180 mg, 4.3 mmol) was added to a stirred solution of 4-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (143 mg, 0.66 mmol) in THF:MeOH:H2O (3:1:1, 5 mL), and the resulting mixture was stirred at room temperature for 8 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with concentrated HCl, filtered the solid precipitated to afford 103 mg (83.06% yield) of 4-Phenyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](/[CH:39]=[CH:40]/[C:41]([O:43]CC)=[O:42])[CH:34]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[C:41](/[CH:40]=[CH:39]/[C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:11]1=[O:31])([OH:43])=[O:42]
Reactant: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)N(Cc2cccc(/C=C/C(=O)O)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 4-(4-cyanophenyl)-3-{3-[(]E)-3-ethoxy-3-oxoprop-1-en-1-yl]benzyl}-6-methyl-l-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 37) (50 mg, 0.08 mmol) in tetrahydrofuran (2 ml) is added a solution of sodium hydroxide (32.4 mg, 0.8 mmol) in water (0.5 ml). After stirring at room temperature for 1 hour, ethanol (2 ml) is added. After 16 hours stirring, the pH of the solution is adjusted to 2 with 1 N hydrochloric acid, and the product is extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90-90:10). The title compound is obtained as a colourless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Li+].[OH-].Cl>C1COCC1.CCO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate (2.5 g, 5.9 mmol; Compound 1) in THF-EtOH (1:1, 59 mL), an aqueous solution of LiOH (2.8 g, 118 mmol; dissolved in a minimum amount of water) was added at room temperature. The resulting mixture was stirred overnight. The reaction was monitored by LCMS. Upon completion, 1N aqueous HCl was added until pH was 3. Then, the mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-20% methanol in dichloromethane affording the title compound as a pale yellow solid (1.9 g). 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.30 (br, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.37 (d, 2H), 7.29-7.11 (m, 6H), 6.88 (d, 2H), 6.37 (d, 1H), 2.44 (q, 2H), 0.87 (t, 3H); LCMS: 395 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][CH2:10]2)[CH:15]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
41.2 mg of the target compound (0.12 mmol, 14.7%) was obtained using 1-(2-methylphenyl)piperazine (289 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: NC1C=C2C(=CC=1N)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.[NH2:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([NH:38][C:39]3[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=3[CH3:47])=[C:31]([C:36]#[N:37])[CH:32]=[N:33]2)=[CH:28][C:27]=1[NH:48][C:49]([NH:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=S.NC1C=C2C(=CC=1NC(NCCN1CCOCC1)=S)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.[S]>O1CCOCC1.C(O)C>[CH3:46][O:45][C:43]1[CH:42]=[CH:41][C:40]([CH3:47])=[C:39]([CH:44]=1)[NH:38][C:30]1[C:29]2[CH:28]=[C:27]3[N:48]=[C:49]([NH:51][CH2:52][CH2:53][N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)[N:25]=[C:26]3[CH2:35][C:34]=2[N:33]=[CH:32][C:31]=1[C:36]#[N:37]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(NC(=S)NCCN4CCOCC4)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(NC(=S)NCCN4CCOCC4)c(N)cc23)c1
Agent: [S]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(C)c(Nc2c(C#N)cnc3c2C=C2N=C(NCCN4CCOCC4)N=C2C3)c1
Temperature: 100 °C

Procedure:
A mixture of 0.1 g (0.3 mmol) of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile and 0.11 g (0.62 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.3 mL of dioxane is heated at 100° C. for 2 hours under nitrogen. The mixture is cooled and solvent is evaporated to dryness to yield an oil consisting of N-[7-amino-3-cyano-4-(5-methoxy-2-methylanilino)-6-quinolinyl]-N′-[2-(4-morpholinyl)-ethyl]thiourea and N-[6-amino-3-cyano-4-(5-methoxy-2-methylanilino)-7-quinolinyl]-N′-[2-(4-morpholinyl)ethyl]thiourea. The oil is dissolved in 3.0 mL of ethanol. To this is added 0.3 g of mercuric oxide and 20 mg of sulphur powder and the resulting mixture is heated at reflux temperature for 2 hours. The product mixture is filtered hot through diatomaceous earth, washed with methanol and solvent is evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 85:15) to yield 0.062 g of 8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,5-g]quinoline-7-carbonitrile as a pink solid, mp 148-150° C. (shrinks at 140° C. ).
Reaction SMILES: CN(C=[O:5])C.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][O:29][CH3:30])=[C:11]([CH:26]=1)[CH:12]([C:15]1[C:20]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)C#N.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][O:29][CH3:30])=[C:11]([CH:26]=1)[C:12]([C:15]1[C:20]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(Br)cc1C(C#N)c1ncccc1C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1ccc(Br)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
DMF (2 ml) was added to a mixture of 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-(1,3-dioxolan-2-yl)pyridine (120 mg) and potassium carbonate (102 mg), which was stirred for 80 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous sodium sulfate) and concentrated to give 2-(5-bromo-2-methoxy methoxy benzoyl)-3-(1,3-dioxolan-2-yl)pyridine (90 mg) (Compound E-1). The physical properties and spectrum data are shown in Table 16 and Table 18.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[CH:5]2[CH2:4]1)[CH3:2].N1CCC[C@H]1C(O)=O.Br[CH:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:28]>CN(C=O)C.[Cu]I>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7](/[CH:26]=[C:27](/[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)\[CH3:28])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CC(=CBr)c1ccncc1
Reactant: CCN1CCC2Nc3ccc(C)cc3C2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2/C=C(\C)c2ccncc2)C1
Temperature: 80 °C

Procedure:
2-Ethyl-8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (150 mg, 0.69 mmol) potassium phosphate (292.5 mg, 1.382 mmol), Copper (I) iodide (13.11 mg, 0.069 mmol) and L-proline (15.8 mg, 0.138 mmol) were mixed in DMF and the purged with nitrogen. The contents were heated at 80° C. for 10 min. 4-(1-Bromoprop-1-en-2-yl)pyridine (208 mg, 1.04 mmol) was added, the reaction mixture was purged nitrogen and heated overnight at 140° C. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by HPLC. 1H NMR (CD3OD, freebase) δ (ppm): 8.58 (d, 2H), 7.70 (d, 2H), 7.35 (s, 1H), 7.30 (s, 1H), 7.05 (m, 2H), 3.95 (s, 2H), 3.10 (q, 2H), 2.95 (m, 4H), 2.42 (s, 3H), 2.00 (s, 3H), 1.30 (t, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:27]6[O:26][CH:30]=[CH:29][CH:28]=6)[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1coc(C2CNCCN2)c1
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Yield: 89.5 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 1-cyclopropyl-7,8-difluoro-3-ethoxycarbonyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.05 g) and (RS)-2-(2-furyl)piperazine (0.6 g). (RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) is obtained in the form of a yellow solid, m.p. 182° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13]([O-:15])=O)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1>CN(C=O)C>[NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13](=[O:15])[N:64]2[CH2:65][CH2:66][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:68][CH2:69]2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.0 g (8.83 mmol) 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.05 g (9.5 mmol) TBTU, 1.28 g (9.47 mmol) HOBT in 1.7 mL (9.76 mmol) ethyldiisopropylamine and 1100 mL DMF was stirred for 1 h at RT. Then 2.2 g (9.51 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were added and the reaction solution was stirred overnight at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in DCM, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. The desiccant was eliminated by filtering through activated charcoal; after elimination of the solvent the desired product was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C(OCC)(=O)C>[CH3:29][N:30]([CH:32]=[C:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reaction time: 1.5 h

Procedure:
A mixture of 0.780 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 10 ml of tert-butoxy bis(dimethylamino)methane (Bredereck's Reagent) is heated on a steam bath while stirring for 1.5 hours (solid dissolved). Cooling gives a solid and the mixture is diluted with ethyl acetate and filtered. The solid is dissolved in dichloromethane-ethyl acetate (7:3) and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane-ethyl acetate (7:3) and the combined filtrate evaporated to give 0.43 g of yellow crystals, Mass Spec (CI) MH+ =366, m.p. 180°-183° C.