Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30](O)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(Cl)CCl.CN.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[C:16]([C:30](=[O:31])[NH:39][CH3:37])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (23 mg, 0.047 mmol) in THF (1 ml) at room temperature under argon was added HOBt (8.0 mg, 0.052 mmol), EDC (10.01 mg, 0.052 mmol), and was followed by 1 M methylamine in THF (0.237 mL, 0.237 mmol). The reaction mixture was stirred at room temperature overnight. EtOAc (10 mL) and 1 N NaOH (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (10 mL), and brine (10 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(methylcarbamoyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (10 mg, white solid, 40.9%). 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H) 1.78-2.05 (m, 4H) 2.96 (d, J=5.27 Hz, 3H) 3.43-3.57 (m, 2H) 3.57-3.72 (m, 2H) 4.49-4.71 (m, 1H) 6.28 (s, 1H) 6.58-6.69 (m, J=3.95 Hz, 1H) 7.46 (dd, 1H) 7.54 (d, 1H) 7.70 (d, J=2.20 Hz, 1H). MS (ESI) 441 (M+H-tBu).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13](Br)[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.O.[F-].[K+]>COCCOC.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>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:32]3[CH:33]=[CH:34][C:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(Br)c3c(N)nccn32)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Temperature: 100 °C

Procedure:
To a stirred mixture of trans-4-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexanecarboxylic acid methyl ester (2.00 g, 5.66 mmol) and 4-phenoxyphenylboronic acid (1.454 g, 6.7 mmol) in DME (25.00 mL) and H2O (8.3 mL) was added potassium fluoride dihydrate (1.865 g, 19.82 mmol). The mixture was bubbled with nitrogen for 5 min before Pd(PPh3)4 (330 mg, 0.28 mmol) was added to. The resulting mixture was refluxed overnight at 100° C. Solvent was removed under reduced pressure and the product was purified by flash chromatography (2% MeOH in DCM). 1H NMR (400 MHz, CD3OD) δ 1.59-1.87 (m, 4H), 2.02-2.18 (m, 4H), 2.41-2.53 (m, 1H), 3.09-3.19 (m, 1H), 3.68 (s, 3H), 6.94-7.20 (m, 6H), 7.32-7.44 (m, 2H), 7.52-7.63 (m, 3H). MS (ES+): m/z: 442.97 [MH+]. HPLC: tR=2.48 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].CCN(CC)CC.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:38][C:39]3[CH:46]=[CH:45][C:42]([CH3:43])=[CH:41][CH:40]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccc(C)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of compound 1 (0.80 g; 1.99 mmol) in CH2Cl2 (20 ml) was added Et3N (0.83 ml; 5.97 mmol) followed by p-methyl benzyl bromide (773 mg; 4.18 mmol). The reaction mixture was stirred overnight and was then was concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.C(N(CC)CC)C.C(O)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:28][C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)=[O:27])[CH3:30]
Reactant: O=C(O)C1CCc2cc(I)ccc2O1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A 2-neck round bottom flask fit with a reflux condenser was charged the compound from Example 28 (1.05 g, 3.45 mmol) and palladium (II) acetate (23 mg, 0.10 mmol). The flask was placed under an atmosphere of carbon monoxide (1 atm). Triethylamine (1.20 mL, 8.63 mmol) and absolute ethanol (2.0 mL) were added via syringe. The dark reaction mixture was heated to 60° C. and stirred for 60 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting dark solution was washed sequentially with 7% aqueous hydrochloric acid, water, and saturated aquesous sodium chloride. The organic layer was dried (MgSO4), and concentrated to an orange oil which crystallized on standing to a pale solid (0.675 g, 81%). 1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.68 (m, 2H), 6.90 (m, 1H), 4.89 (m, 1H), 4.25 (q, J=7.36 Hz, 2H), 2.82 (m, 1H), 2.66 (m, 1H), 1.28 (t, J=6.98 Hz, 3H); MS (CI) m/z 251 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[N:12]O)[CH2:7]1.C1(C)C(S(Cl)(=O)=[O:27])=CC=CC=1.S(=O)(=O)(O)O.C(Cl)Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][NH:12][C:8](=[O:27])[CH2:7]1
Reactant: Cc1cc(C)c(CSC2CCCC(=NO)C2)c(C)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(CSC2CCCNC(=O)C2)c(C)c1

Procedure:
A solution of 828 mg of 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime and 570 mg of toluenesulfonylchloride in 5 ml of pyridine is stirred at RT for 4 hours and additional 2 hours at 60°. The mixture obtained is distributed between diluted sulfuric acid (2 ml H2SO4 conc. in 15 ml H2O) and CH2Cl2, the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepan-2-one is obtained. 1H-NMR(d-6-DMSO): 7.5 (m,1H,NHCO), 6.8 (s,2H,arom.H), 3.75 (s,2H,C6H5CH2S—),3.2 (m, 1H,CHN), 3.1(m,3H, CH2NH,CHS)AB-system: vA=2.72,vB=2.65(2H,CH2C═O, J=13.4 Hz, J=4.5 Hz) 2.13 2.15,2.3(9H, 3×CH3)
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](OCC)=[O:23])[C@@H:18]([C:27](OCC)=[O:28])[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[BH4-]>C1COCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:27][OH:28])[C@@H:17]2[C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:8]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 68 °C
Yield: 95.4 %

Procedure:
To a solution of 9.2 g (15.9 mmol) diethyl (1S,2S,3R,4S)4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate (step F) in 100 mL THF under nitrogen atmosphere at RT was added 2 g (112.4 mmol, excess) LiBH4 powder. The resulting mixture was heated at 68° C. for 2 hr then cooled to RT. The reaction mixture was carefully quenched by the addition of 30 mL water, then extracted with EtOAc. The combined organic extracts were dried over drying agent, filtered and the solvent evaporated under vacuum to give 7.5 g of the crude title compound as an oil which was used without further purification. 1H-NMR (CDCl3): δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.87 (2H, t, J=8.2 Hz), 4.20 (1H, q, J=6.0 Hz), 3.78 (1H, m), 3.67 (1H, m), 3.52 (1H, m), 3.30-3.20 (2H, m), 2.58 (1H, t, J=11.9 Hz), 2.32 (1H, m), 1.87 (1H, m), 1.65 (1H, m), 1.58-1.35 (3H, m), 1.30 (3H, t, J=6.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:37][CH:38]=1
Reactant: O=C(CO)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C(=O)CO)CC4)sc3n2)cn1

Procedure:
1-(4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (265 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 16.5 mg of 181. MS (Q1) 470.2 (M)+
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1>ClCCl>[OH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(NC(C)=O)nc23)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1

Procedure:
Trifluoroacetic acid (0.10 mL, 1.3 mmol, Aldrich) was added dropwise to a solution of N-{4-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 136(b)), (0.50 g, 1.0 mmol) in dichloromethane (10 mL) with stirring and cooling in an ice bath. The reaction mixture was stirred for 16 h at room temperature, diluted with dichloromethane (5 mL) and quenched with satd sodium bicarbonate solution. The reaction mixture was diluted with water (100 mL), extracted with dichloro-methane (2×100 mL), and the combined organic extracts were concentrated in vacuum. The resulting white solid was suspended in MeOH (50 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 302–304° C. MS (ESI, pos. ion.) m/z: 445 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:14][CH2:15][CH2:16][CH:17]([NH:21][C:11]([C:3]1[C:2]([CH3:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc2c(cc1C(=O)O)OCO2
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1cc2c(cc1C)OCO2

Procedure:
Prepared in a similar manner to example 4 using 6-methylbenzo[d][1,3]dioxole-5-carboxylic acid and heptan-4-amine. MS (M+H, 278.67).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: C=CC(=O)OC
Product: COC(=O)CCNc1cccc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
In a round bottom flask was added 3-aminobiphenyl 2.6 g (15.3 mmol), methyl acrylate 1.5 g (16.9 mmol) and cupric acetate 0.1 g, the reaction mixture was stirred 5 hour at 90° C., another 5 equivalent of methyl acrylate 7 g (75 mmol), and 0.25 g of cupric acetate was added, and the reaction mixture was heated for another 5 hours. The crude was purified using silica gel chromatography using 15% of ethyl acetate and petroleum ether. Yield to 1.6 g of oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=1)=O.[OH-].[K+].CC(O)=O>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:7]2[NH:18][C:16](=[O:17])[C:11]3[C:10](=[N:15][CH:14]=[CH:13][N:12]=3)[N:9]=2)[CH:19]=1
Reactant: NC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxamide 103 (2.3 g, 6.78 mmol) and KOH (3.81 g, 67.8 mmol) in H2O (60 mL) and DMSO (20 mL) was stirred at room temperature for 45 min. Acidification to pH 5 (pH paper control) with AcOH followed by addition of 50 mL of ice-cold water afforded a precipitate, which was filtered off, washed with H2O, acetonitrile and ether to give 1.83 g of the title product 104 as a white powder (LCMS analysis).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1>C1(C(C)C)C=CC(C)=CC=1.[Pd]>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1
Reactant: CCCc1c2c(cc3c(Cl)cc(C(=O)OC)nc13)C(=O)CC(C(=O)OCC)O2
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Yield: 6.7 %

Procedure:
Ethyl 6-chloro-2,3-dihydro-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (0.405 g) was suspended in cymene (10 ml) and refluxed with Pd/C (5%, 0.200 g) for 10 hours. The whole was filtered hot, to remove the catalyst, cooled, poured into petroleum ether (40°-60°, 40 ml), to give a pale buff solid, which was chromatographed of silica, to give the title compound, (0.027 g) mp 174°-176°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[N:6]=1.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>C1COCC1.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:5]1[N:6]=[CH:2][S:3][C:4]=1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1nc(C2OCCO2)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1scnc1C1OCCO1
Yield: 98.1 %

Procedure:
2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g, 27.14 mmol) was stirred at −78° C. in dry THF (38 ml). 1.6M n butyl lithium in hexane (18.6 ml, 29.78 mmol) was added dropwise under nitrogen. After 30 min at this temperature, tributyl tin chloride (7.35 ml, 27.14 mmol) was added dropwise. The reaction was allowed to warm to 0° and water (20 ml) was added. The product was extracted into ether (3×100 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was triturated with isohexane (3×100 ml) and the mother liquors were decanted, combined and concentrated to give a brown oil (11.88 g); m/z 444-450.
Reaction SMILES: CON(C)[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]([CH3:8])[CH3:7].C[Li].[CH3:21]C#N>C1COCC1.C(=O)=O.CCOC(C)=O.O>[CH3:8][CH:6]([C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:4](=[O:17])[CH3:21])[CH3:7]
Reactant: CC#N
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: O=C=O
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-tert-butyl 1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (4.23 g, 16.25 mmol) in THF (100 mL) at −70° C. was added drop wise methyl lithium (1.071 g, 48.7 mmol). Cold bath was replaced with −40° C. bath (MeCN in dry ice) removed and the reaction was stirred for 4 hours. Saturated NH4Cl solution (10 mL) was then added cautiously to quench the reaction. The reaction mixture was then allowed to warm to room temperature, and diluted with EtOAc (100 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (3.01 g). LCMS m/z 238.2 (M+Na)+, Rt 0.78 min.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[I:15]Cl>C(O)(=O)C>[I:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: ClI
Solvent: CC(=O)O
Product: O=C1C(=O)N2CCCc3cc(I)cc1c32
Temperature: 0 °C

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (5 g) and iodine monochloride (5 g) in acetic acid (30 ml) was refluxed for 5 hours. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and then dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from ethanol to give 6.2 g (73.8%) as dark red needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[C:14]1([CH3:26])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:23]1[CH2:24][CH2:25][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:26])[CH2:21][CH2:22]1)[CH2:7][CH2:6]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(N1CCN(c3ccccc3C)CC1)C2

Procedure:
3.6 g of 6-methoxy-2-tetralone are dissolved together with 3.9 g of N-(o-tolyl)-piperazine in 50 ml of acetic acid, 1 g of a 10% palladium on charcoal catalyst is added and hydrogenation effected. When the take-up of hydrogen ceases, the catalyst is filtered off, the solvent evaporated and the residue chromatographed on Kieselgel in manner analogous to that described in Example 1. The title compound is obtained as a compact residue. M.P. 286°-288° [Hydrochloride salt form].
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)C)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[CH3:1][NH:8][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1
Reactant: CN(CCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Yield: 100.1 %

Procedure:
A mixture of 1-[1-{4-[3-(N-benzyl-N-methylamino)-propoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (5.3 g), 5 % palladium-carbon (0.8 g), ammonium formate (2.6 g) and ethanol (300 ml) is refluxed with heating for 2 hours. The catalyst is filtered off and ethanol is distilled off under reduced pressure. To the residue is added chloroform and the mixture is washed successively with saturated sodium hydrogen carbonate, water and saline solution. Further the mixture is dried with sodium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol =20:1→5:1) to give 1-[1-{4-[3-(N-methylamino)propoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (4.37 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1
Reactant: BrCCCC/C=C\C=C/CCCCBr
Reactant: Cc1ccncc1C
Solvent: CC#N
Product: Cc1cc[n+](CCCC/C=C\C=C/CCCC[n+]2ccc(C)c(C)c2)cc1C
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 3,4-lutidine (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no 3,4-lutidine left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.34 (s, 1H), 8.29 (d, J=6.3, 1H), 7.60 (d, J=6.3, 1H), 6.13-6.18 (m, 2H), 5.30-5.38 (m, 2H), 4.31 (t, J=7.2, 4H), 2.37 (s, 3H), 2.25 (s, 3H), 2.05 (q, J=7.2, 4H), 1.81 (p, J=7.5, 4H), 1.24 (p, J=7.5, 4H). CNMR, 158.66, 142.37, 140.71, 138.65, 132.25, 128.23, 124.07, 60.80, 30.11, 26.31, 25.42, 19.69, 16.34.