Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)[CH:12]=1
Reactant: CS(=O)(=O)c1ccc(OCCCBr)cc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 73.1 %

Procedure:
A mixture of 1.0 g (1.92 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.84 g (2.88 mmol) of 1-(3-bromopropoxy)-4-(methylsulfonyl) benzene, 0.53 g (3.83 mmol) of potassium carbonate and 0.3 g (1.92 mmol) of sodium iodide in 30 ml of acetone and 6 ml of DMF was stirred at refluxunder argon for 72 hours. The solvents were removed at reduced pressure andthe residual oil was purified by three recrystallizations from methylene chloride-methanol to give 1.03 g (73% yield, mp 70°-72°) of N-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)-phenyl]glycine methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8].C(N(CC)CC)C>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:14])([O-:9])=[O:8]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Cn1cccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 45.9 %

Procedure:
A solution of 1-methylpyrrole (10.0 g, 123.0 mmol), 3-nitrobenzoyl chloride (68.47 g, 369 mmol), and triethylamine (17.14 ml, 123 mmol) in xylenes (150 ml) was refluxed for 40 h. Purification of the reaction mixture on a Florisil® column (hexane-acetone, 85:15) gave 2-(3-nitrobenzoyl)-1-methylpyrrole (13.0 g, 46%) as a solid. ##STR42##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:12](=[N:14]\[OH:15])\[NH2:13])[CH:5]=[CH:4][CH:3]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:12]2[NH:13][C:27](=[O:28])[O:15][N:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=N\O)/C(=N\OCc1cccc(N)n1)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of (1Z,2Z)-2-{[(6-aminopyridin-2-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (3 g, 10.51 mmol, 1 eq.) in DMF (50 ml) was added CDI (1.70 g, 10.51 mmol, 1 eq.) and stirring at room temperature was allowed for 30 min before heated to 80° C. for 6 h. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was triturated in MeCN and a white solid was isolated by filtration giving a first crop of 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (1.36 g, 36% yield). The mother liquor was concentrated and purified by chromatography on silica gel to give a second crop (2.9 g, 50% purity, 40% yield).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([C:24]#[N:37])[CH2:20][CH2:19]2)[CH2:17]1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Reactant: N#CBr
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 1.0 g of 1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 17 in 16 ml of dry chloroform is added 2.4 g of anhydrous potassium carbonate and 0.73 g of cyanogen bromide. The reaction is stirred 7 hours at room temperature and then is filtered through paper. Approximately one ml of methanol is added and the solution is rotary evaporated to a glass. The glass is chromatographed on 80 cc of silica gel with 1:1, ether:dichloromethane to give a crystalline solid. The solid is recrystallized thrice from acetone-hexane to give a solid of 1-(2-chlorophenyl)-1'-cyanospiro(indoline-3,4'-piperidine), mp 157.5°-159.5° C.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.[NH4+:26].[Cl-]>C(O)C>[C:20]1([C:2]2[N:26]=[C:5]([CH:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Agent: [Cl-]
Solvent: CCO
Product: c1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Microwave heat a mixture of tert-butyl 4-(2-oxo-2-phenylethylcarbamoyl)-piperidine-1-carboxylate (1.0 g, 2.88 mmol) and NH4Cl (0.462 g, 8.65 mmol) in ethanol (12 mL) at 300 W, 160° C., and 14 bar for 11 h in a Personal Chemistry microwave. Cool the mixture to room temperature, add silica gel (5 mL), and concentrate the mixture in vacuo. Purify the residue by silica gel chromatography (80 g RediSep column, elute with a gradient of 0% through 100% CMA/methylene chloride over 60 min, 60 mL/min) to provide 4-(4-phenyl-1H-imidazol-2-yl)piperidine (0.418 g, 64%) as an off-white solid. Add 4-(4-phenyl-1H-imidazol-2-yl)piperidine (0.060 g, 0.26 mmol) to methylene chloride (15 mL) and concentrated hydrochloric acid (28 μL). Stir the mixture for 45 min, then concentrate the mixture in vacuo to provide 4-(4-phenyl-1H-imidazol-2-yl)piperidine hydrochloride (0.070 g, 99%).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CC(C)([O-])C.[K+]>CN(C)C=O>[C:25]([C:24]1[CH:23]=[C:22]([CH2:21][N:9]2[C:8](=[O:13])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]2=[O:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2C(=O)NC(c3ccccc3)(c3ccccc3)C2=O)c1

Procedure:
Prepared by reacting 25.5 g (0.101 Mol) of 5,5-diphenylhydantoin with 21.15 g (0.108 Mol) of 3-(bromomethyl)-benzonitrile in the presence of 12.0 g (0.107 Mol) of potassium tert.-butoxide and 200 ml of anhydrous dimethylformamide. After conventional working up 34.0 g (92% of theory) of colourless crystals were obtained, mp. 160°-164° C.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][CH:9]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:15]([CH3:29])[C:14]1=[O:30])[CH2:10][O:11][CH3:12])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][CH2:8][CH:9]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[CH:15]([CH3:29])[C:14]1=[O:30])[CH2:10][O:11][CH3:12]
Reactant: COCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCC(CCO)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Yield: 53.1 %

Procedure:
To a solution of 1-[3-(tert-butyl-diphenyl-silanyloxy)-1-methoxymethyl-propyl]-3-methyl-4-(3-trifluoromethyl-phenyl)-piperazin-2-one (139 mg, 0.23 mmol) in THF (3 mL) was added tetrabutylammonium fluoride solution (1 M in THF, 0.28 mL, 0.28 mmol) at 0° C., then after 2 h the reaction mixture was partitioned between sat. aq. NaHCO3 solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc/MeOH 19:1) afforded the title compound (44 mg, 52%) as a colorless oil.
Reaction SMILES: BrC1C=CC(C2C=CC(OC(=O)C3C=CC(OC(C)CCCCCC)=CC=3)=CC=2)=CC=1.C(OC(C1C=CC(C2C=CC(O)=CC=2)=CC=1)=O)C.[OH-].[K+].FC1C=CC([O:59][C:60]([C:62]2[CH:67]=[CH:66][C:65]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH:75]([CH3:82])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])=[CH:70][CH:69]=3)=[CH:64][CH:63]=2)=[O:61])=CC=1.C(OC(C1C=CC(C2C=CC(OC(C)CCCCCC)=CC=2)=CC=1)=O)C.[OH-].[Na+].Cl>CO.O.C(O)C.C1(C)C=CC=CC=1>[CH3:82][CH:75]([O:74][C:71]1[CH:72]=[CH:73][C:68]([C:65]2[CH:64]=[CH:63][C:62]([C:60]([OH:61])=[O:59])=[CH:67][CH:66]=2)=[CH:69][CH:70]=1)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81]
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)Oc3ccc(F)cc3)cc2)cc1
Agent: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Agent: CCCCCCC(C)Oc1ccc(C(=O)Oc2ccc(-c3ccc(Br)cc3)cc2)cc1
Agent: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 12 %

Procedure:
Preparation of optically active p-(1-methylheptyloxy)benzoic acid 4'-bromo-4-biphenylyl ester (a compound of the formula (I) wherein l=1, m=1, R=C6H13, X=Br and Y, Z=H; Sample No. 9) P-hydroxybenzoic acid methyl ester (IV) (28.5 g, 0.187 mol) was dissolved in methanol (120 ml), and KOH (10.1 g, 0.187 mol) was added to and dissolved in the solution, followed by adding to the resulting solution, optically active p-toluenesulfonic acid 1-methyl-heptyl ester (III) (58.6 g, 0.206 mol) obtained in Example 1, keeping the mixture under reflux for 4 hours, then cooling, adding toluene (200 ml) and 6N--HCl (50 ml), washing the resulting toluene layer with 2N--NaOH aqueous solution and then with water till the washing water became neutral and distilling off toluene to obtain as a residue, optically active p-(1-methyl-heptyloxy)benzoic acid methyl ester (V) (14.2 g). This ester (14.2 g, 0.054 mol) was dissolved together with ethanol (5 ml), NaOH (3.2 g, 0.081 mol) and water (20 ml), followed by heating the solution under reflux for one hour, then cooling, pouring the reaction fluid in 6N--HCl aqueous solution (50 ml) with stirring, filtering off deposited crysrals and recrystallizing from ethanol to obtain optically active p-(1-methyl-butyloxy)benzoic acid (VI) (8.1 g) having a melting point of 61.2°~63.1° C. To this product (7.5 g, 0.030 mol) was added thionyl chloride (6.0 g, 0.047 mol), followed by heating the mixture under reflux for one hour, and distilling off excess thionyl chloride to obtain opticaly active p-(1-methyl-heptyloxy)benzoic acid chloride (VII) (5.8 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
To 60 ml of an ethanol solution of 4.040 g (12.19 mmol) of 1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-pyrrolidine-2-thione (isomer B1) was added 20 ml of Raney nickel, followed by stirring at room temperature for 40 minutes. Any insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the mixture was washed with 10% aqueous ammonia. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2.988 g (81.3%) of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2Cl)[CH:16]=1>O1CCCC1>[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2[NH:4][C:3]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])[CH:16]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(Br)sc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(Br)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (221.8 mg, 1.16 mmol) and 60% sodium hydride (46.2 mg, 1.16 mmol) in 6 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile (150 mg, 0.55 mmol) is added. The resulting reaction mixture is heated at reflux for 5 hours, cooled to room temperature, and then partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 40% ethyl acetate in hexane to provide 114.6 mg of 2-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 228–229° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.71 (s, 1H), 7.80 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H); MS 426.0, 428.0 (M−H)−.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:10](OCC)=[O:11])=[C:7]([CH3:9])[N:8]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]([C:4]1[S:5][C:6]([CH2:10][OH:11])=[C:7]([CH3:9])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(C(C)C)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(C)C)sc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of ethyl 2-isopropyl-4-methyl-1,3-thiazole-5-carboxylate (2.42 g) in THF (50 mL) was added lithium aluminum hydride (0.431 g) at 0° C. The mixture was stirred at 0° C. under argon atmosphere for 1 h. To the mixture was added sodium sulfate decahydrate and the mixture was stirred for 10 min. The precipitate was filtered off through celite and the filtrate was concentrated in vacuo to give the title compound (1.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:2].[N:15]([O-:17])=[O:16].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:15]([O-:17])=[O:16])[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:2]
Reactant: CCOc1ccc2c(c1)CCC(=O)N2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To the solution of 6-ethoxy-3,4-dihydroquinolin-2(1H)-one (72.3 g, 0.38 mol, 1 equiv) in TFA (800 mL) was added NaNO2 (33.7 g, 0.496 mol, 1.3 equiv) at 0° C. The solution was allowed to warm to room temperature and stirring was continued for 4 hours. The mixture was poured into ice and the yellow precipitate was isolated via filtration and dried under high vacuum at 50° C. The crude product was recrystallized from ethyl acetate to afford 6-(ethyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (69.2 g, 77% yield). 1H NMR (400 MHz, DMSO) δ 1.31 (t, J=6.8 Hz, 3H), 2.45-2.49 (m, 2 H), 2.95 (t, 2 H, J=6.4 Hz), 4.13-4.15 (m, 2 H), 7.25 (s, 1 H), 7.34 (s, 1 H), 10.16 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:12][CH3:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(OCC)C>[NH2:18][C:2]1[CH:3]=[C:4]([C:9]([O:12][CH3:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1cc(Br)ncc1OC
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(N)ncc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (9.30 mg, 0.0102 mmol), 2-(dicyclohexylphosphino)biphenyl (3.56 mg, 0.0102 mmol), and methyl 2-bromo-5-methoxyisonicotinate (50 mg, 0.203 mmol) obtained in step 2 were suspended in toluene (0.5 mL), and the suspension was stirred at room temperature for 3 hours after adding lithium bis(trimethylsilyl)amide (1 mol/L THF solution) (0.224 mL, 0.224 mmol). The reaction mixture was stirred at room temperature for 10 minutes after adding diethyl ether (10 mL) and 1 mol/L hydrochloric acid (0.1 mL). Then, a 1 mol/L sodium hydroxide aqueous solution (5.0 mL) was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give methyl 2-amino-5-methoxyisonicotinate (20.0 mg, yield 54%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:30]5[C:31]6[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=6)[N:27]=[CH:28][CH:29]=5)=[O:38])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, light brown solid (98 mg, 82%), MS (ISP) m/z=484.5 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8](I)[CH:9]=[CH:10][CH:11]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].C(C#N)(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1cccc(I)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Solvent: O
Product: CN(C)CCOc1cccc(-c2ccc(C(=O)O)cc2)c1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
Stirred a solution of 3-(2-Dimethylaminoethoxy)phenyl iodide (0.495 g, 1.70 mmoles), 4-carboxybenzeneboronic acid (Lancaster, 0.282 g, 1.70 mmoles), and sodium carbonate (0.360 g, 3.40 mmoles) in 1:1 H2O: AcCN (20 mL) under vacuum for five minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (0) (0.170g). The reaction mixture was heated (90° C.) for three hours, and the catalyst was filtered off through Celite. The effluent was concentrated slightly to remove the AcCN, and the resulting aqueous solution was acidified with 2N HCl and purified on an HPLC to yield 0.462 g of the title compound as the TFA salt. MS (ion spray) m/z 286 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl>[O:18]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Oc1cccc2cccnc12
Reactant: Brc1cccc2cccnc12
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1cnc2c(Oc3cccc4cccnc34)cccc2c1
Yield: 19 %

Procedure:
The product has already been described in: V. M. Dziomko et al., Yakugaku Zasshi 1951, 71, 452-455; but using a different method of synthesis. Caesium carbonate (156 mg; 0.48 mmol), 8-bromoquinoline (32 μl; 50 mg; 0.24 mmol) and CuCl2.2H2O (4.1 mg; 0.024 mmol) are added to a solution under argon of 8-hydroxyquinoline (71 mg; 0.49 mmol) in 2.0 ml of dry DMF. The mixture is heated under reflux for 72 hours. After cooling, 5 ml of CH2Cl2 and 5 ml of a 0.12 M aqueous solution of EDTA disodium salt are added. The organic phase is recovered and the aqueous phase is subsequently extracted with CH2Cl2 (2×5 ml). The organic phases are combined and washed once with 5 ml of 0.12 M EDTA in H2O then in water. The volume is reduced under reduced pressure then the reaction crude product is purified by silica gel chromatography, eluted with a gradient of 50 to 100% of ethyl acetate in toluene (v/v) then with 100% of CH3OH and the solvent is evaporated to recover 15, from the methanol phase, in the form of a white powder (13 mg; 0.046 mmol, yield=19%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.95 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 2H); 8.21 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 2H); 7.61 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.0 Hz, 2H); 7.46 (dd, 3J (H, H)=4.0 Hz and 8.5 Hz, 2H); 7.42 (dd, 3J (H, H)=7.5 Hz and 8.0 Hz, 2H); 7.14 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.0 Hz, 2H). MS (CID, NH3): m/z=273 (MH+). UV/vis [CH3OH/20 mM Tris-HCl pH=7.4 containing 150 mM NaCl (1/1, v/v)]: λ nm (ε M−1 cm−1)=232 (53,300), 240 (42,900), 2994 (9,400), 327 (5,800, shoulder).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cu][C:13]#[N:14]>CN(C)C=O.N1C=CC=CC=1>[C:13]([C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4])#[N:14]
Reactant: N#C[Cu]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])cc1N
Temperature: 160 °C
Yield: 70.4 %

Procedure:
To a solution of 2-bromo-5-nitroaniline (5.0 g, 23 mmol) in dimethylforamide (100 ml) and pyridine (20ml) was stirred with copper(I) cyanide (2.05 g, 64 mmol). The mixture was then heated to 160° C. for 48 hrs. The reaction was then cooled to room temperature and filtered through celite, the celite was washed with ethyl acetate. The solvent was evaporated and chromatography of the resulting solid on silica gel (25%EtOAc/Hexane) gave the desired product (2.64 g, 70%). 1H NMR (CD3COCD3): δ7.75 (s, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 6.25(bs, 2H).