Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Cn1ncc2cc(B(O)O)ccc21
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(cnn4C)c3)ccn2c1=O
Yield: 98.5 %

Procedure:
Methyl 8-(1-methyl-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (176.0 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (129.8 mg, 95%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([F:26])([F:25])[F:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-].CO>[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]([F:26])([F:24])[F:25])[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(5-fluoro-2-(trifluoro-methyl)phenyl)quinoline hydrochloride (0.3482 g, 0.8480 mmol) in DMF (4.240 mL, 0.8480 mmol) was added sodium azide (0.1103 g, 1.696 mmol) at room temperature and the mixture was stirred at room temperature. After 1.5 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1 H, s), 8.12 (1 H, dd, J=8.3, 1.3 Hz), 7.99-8.06 (2 H, m), 7.69 (1 H, dd, J=8.1, 7.5 Hz), 7.58-7.66 (2 H, m), 4.44-4.59 (2 H, m); LC-MS (ESI) m/z 381.1 [M+H]+. To a solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)-quinoline (0.2573 g, 0.676 mmol) in methanol (6.76 mL, 0.676 mmol) was added palladium, 10 wt. % on activated carbon (0.0360 g, 0.0338 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2 After 30 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give green syrup. The green syrup was purified by column chromatography on a 40 g of Redi-Sep™ column using 0% to 20% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min, and then 20% isocratic of CH2Cl2:MeOH:NR4OH (89:9:1) for 20 min as eluent to give (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1 H, s), 8.04 (1 H, dd, J=8.4, 1.2 Hz), 8.01 (1 H, dd, J=8.5, 5.4 Hz), 7.93 (1 H, dd, J=7.4, 1.4 Hz), 7.54-7.67 (3 H, m), 3.48-3.74 (2 H, m), 1.96 (2 H, br. s.); LC-MS (ESI) m/z 355.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:12]=1[NH2:13].[CH:22]([C:34]1[CH:35]=[N:36][N:37]([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](O)=[O:41])[CH:38]=1)=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.ClCCl>[CH:22]([C:34]1[CH:35]=[N:36][N:37]([CH:39]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:40]([NH:13][C:12]2[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[O:10][CH3:9])=[O:41])[CH:38]=1)=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC=Cc1cnn(C(C(=O)O)c2ccccc2)c1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Triethylamine (18 mL, 130 mmol) was added to a suspension of 2,4,6-trimethoxyaniline hydrochloride (28.48 g, 130 mmol) in 500 mL THF and stirred for 1 hour before filtering to remove triethylamine hydrochloride. The filtrate was concentrated and redissolved in 500 mL dichloromethane along with (±)-4-(1-dodecenyl)-α-phenyl-1H-pyrazole-1-acetic acid (43.43 g, 118 mmol) at -15° C. Dicyclohexylcarbodiimide (25.53 g, 124 mmol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Filtered to remove a white solid and partitioned the filtrate between dichloromethane and 1N HCl. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily tan solid. Recrystallized from hexanes to give the title compound as a tan solid (45.43 g, 72%); mp 82°-85° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]3[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:24][C:17]=3[N:16]([CH3:34])[S:15]2=[O:35])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:16]1[S:15](=[O:35])[N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:36])=[O:5])=[CH:12][CH:11]=2)[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:23]=[CH:24][C:17]1=2
Reactant: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)S1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)O)cc2)S1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A solution of 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2λ4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid tert-butyl ester (0.33 g, 0.66 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (3 mL), and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, treated with hot ethyl acetate, allowed to cool, and the solid collected by filtration. The solid was triturated with ethyl ether, the solid collected by filtration, and allowed to air dry under house vacuum. The process afforded 0.03 g of 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2λ4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid as a blue/green solid (9.5% yield. 1H-NMR (CDCl3); d 8.30 (d, 1H), 8.08-8.06 (d, 2H), 7.69-7.67 (dd, 1H), 7.48-7.46 (d, 2H), 7.40-7.32 (m, 4H), 7.27-7.23 (m, 1H), 6.97-6.95 (d, 1H), 5.44-5.40 (d, 1H), 4.81-4.77 (d, 1H), 3.83 (s, 2H), 3.41 (s, 3H). MS: M++1=445.1 Da
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=3)=[O:21])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (8.83 g, 47.9 mmol) and 4-bromobenzoyl chloride (10.0 g, 45.6 mmol) were dissolved in anhydrous dichloromethane (240 mL) followed by addition of N,N-diisopropylethyl amine (8.74 mL, 50.2 mmol) dropwise over the course of 30 minutes. After stirring at room temperature for four hours, the reaction mixture was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue from ethyl acetate afforded the title compound (15.4 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[C@@H:22]1[CH2:26][O:25]C(C)(C)[O:23]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:23][C@H:22]([C@@H:7]1[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:3]=1[O:2][CH3:1])[CH2:26][OH:25]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)c(OC)c1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-3-yl)carbamate (267 g, 0.567 mol) in THF (3 L) was added a solution of TsOH.H2O (43.6 g, 0.229 mol) in water (0.75 L). The bilayer was heated to 70° C. for 16 h then cooled to rt, neutralized to pH=7 with saturated NaHCO3 (aq) and concentrated in vacuo. The resulting mixture was filtered, washed with water and dried to afford the title compound (240 g, 98%) as a pale yellow solid. LCMS: m/z=431.1 (M+1).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:18][C:43](=[O:44])[C:42]([S:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:46]([OH:47])[CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Oc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1)c1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzoyloxyacetophenone (1.27 g, 5.31 mmol), lithium bis(trimethyl-silyl)amide (0.977 g, 5.84 mmol), chlorotrimethyl-silane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54. mmol). m.p. dec. 205° C.; 1H NMR (400 MHz, DMSO-d6) δ4.01 (s, 2 H), 6.75 (s, 1 H), 7.21 (m, 1 H), 7.25 (d, 4 H), 7.47 (d, 2 H), 7.63 (t, 2 H), 7.77 (t, 1 H), 7.90 (d, 2 H), 8.16 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:37]1([CH2:42][CH2:43]N)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[N:37]1([CH2:42][CH2:43][NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NCCN1CCCC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN3CCCC3)cc21
Reaction time: 18 h
Yield: 63 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 2-pyrrolidin-1-yl-ethylamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-7 as an oil in 63% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:15]1([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (R)-3-(tert-butoxycarbonylamino)piperidine (0.10 g, 0.50 mmol), phenylboronic acid (0.13 g, 1.1 mmol) and copper (II) acetate (0.10 g, 0.551 mmol) in DCM (2 ml) under air was charged with triethylamine (0.14 ml, 1.0 mmol), sealed and stirred at RT for 18 hours followed by stirring at 60° C. for 72 hours. The reaction mixture was filtered through celite and eluted with DCM/MeOH. The filtrate was concentrated in vacuo and purified by flash chromatography (Biotage, 0-20% MeOH/DCM) to provide tert-butyl [(3R)-1-phenylpiperidin-3-yl]carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[CH2:12][CH2:13][C@H:14]([OH:16])[CH3:15].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[OH:16][C@H:14]([CH3:15])[CH2:13][CH2:12][C:3]1[C:4]([O:8][CH2:9][O:10][CH3:11])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1cccc(N)c1CC[C@@H](C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1cccc(NC(C)=O)c1CC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
A solution of crude (R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol (2.60 g, 11.54 mmol) and pyridine (2.80 mL, 34.6 mmol) in dichloromethane (52 mL) was cooled to 0° C. and treated with acetic anhydride (1.14 mL, 12.1 mmol). The ice bath was removed and the reaction mixture stirred at room temperature. After 45 min, the solution was washed with 5% aqueous sodium chloride solution (2×20 mL) and then concentrated under reduced pressure. Toluene (ca. 100 mL) was added and the mixture was concentrated. The residue was purified by column chromatography on silica gel (gradient elution with 25-100% ethyl acetate-hexanes) to afford (R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide (2.7 g, 88%) as a pale yellow syrup. MS (ESI, pos. ion) m/z 290 [M+23]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:16][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(cc1C(=O)O)CCCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester (1.6 g) in methanol (25 ml) is treated with N sodium hydroxide (8 ml) and heated at reflux temperature for 4 hours. The solution is concentrated, diluted with water and the solution is extracted with ethyl acetate. The washed extract is dried and evaporated to a viscous residue which crystallizes after trituration with ether. Recrystallization of the product (0.119 g) from methanol-ethyl acetate solution gives pure 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid, m.p. 196° C.-197° C.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:10]([O:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1.[N:21]#[C:22][NH2:23].[Na].C1OCCOCCOCCOCCOCCOC1>CC(CC(=O)C)C>[C:22]([NH:23][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:10]([O:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CN
Reactant: COc1cc(-c2ccc(Br)nn2)ccc1OCC(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC(=O)CC(C)C
Product: COc1cc(-c2ccc(NC#N)nn2)ccc1OCC(C)C

Procedure:
3 g 3-bromo-6[4-(2-methylpropoxy)-3-methoxyphenyl]pyridazine, 1.3 g sodium cyanamide and 0.5 g 18-crown-6 are boiled under reflux in 30 ml 2-methyl-4-pentanone for 5 hours. The reaction solution is then evaporated in vacuo and the residue is boiled up briefly with 200 ml 2N sodium hydrogen sulphate solution, while stirring thoroughly, the reaction product precipitating as a fine crystalline precipitate. The precipitate is filtered off with suction and boiled up again with isopropanol, the mixture is cooled and the product is filtered off with suction and, after washing with isopropanol and petroleum spirit (b.p. 50°-70° C.), dried in vacuo. This gives 2.5 g (80.6%) of the title compound of m.p. 191° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.Cl.[C:42]([O:46][C:47](=[O:50])[CH2:48][NH2:49])([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:42]([O:46][C:47](=[O:50])[CH2:48][NH:49][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ncccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
To a solution of 3-hydroxypicolinic acid (0.20 g, 1.44 mmol) in DMF (5 mL) at 0° C. under N2 is added diisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.412 g, 2.9 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.019 g, 0.14 mmol). The resulting mixture is stirred for 5 min before glycine tert-butyl ester HCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirred at room temperature for 3 days then concentrated under reduced pressure. The reaction mixture is diluted with EtOAc then washed with 1M HCl, sat. NaCl, and the organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to a crude oil that is purified over silica (EtOAc/heptane 1:4) to afford 0.078 g (22% yield) of the desired compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.80 (1H, s), 8.39 (1H, br s), 8.02 (1H, dd, J=4.4, 1.5 Hz), 7.27 (1H, dd, J=8.8, 4.4 Hz), 7.25 (1H, dd, J=8.4, 1.5 Hz), 4.06 (2H, d, J=5.5 Hz), 1.44 (9H, s). HPLC-MS: m/z 197 [M-tBu]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]1=2.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.N1CCCCC1>C(O)(=O)C>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)c1ccc2c(c1)CCCC2=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)CCC(=Cc1cccnc1)C2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
5.0 g of ethyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 2.5 g of 3-pyridinealdehyde, 10 ml of acetic acid and 10 ml of piperidine and then the mixture was stirred at 100° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. 10% Hydrochloric acid was added to the solution. The aqueous layer was separated and neutralized by addition of sodium bicarbonate. The mixture was extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5.6 g of ethyl 6-(3-pyridylmethylidene)-5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as pale yellow crystals with m.p. 112°-114° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:35][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33](=[O:34])[O:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:3]3[C:4]([CH3:13])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:6]=[C:2]3[NH2:1])=[CH:19][CH:18]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1c(-c2ccccc2)nc(N)n1-c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3c(N)nc(-c4ccccc4)c3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
A mixture of 2-[4-(2-amino-5-methyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethanol (100 mg, 0.34 mmol) and p-toluenesulfonylisocyanate (67 mg, 0.34 mmol) in dichloromethane (5 mL) was stirred at 0° C. for 10 min. It was washed with water and organic phase was dried over Na2SO4. After removal of solvent, the residue was purified by TLC with dichloromethane/methanol (10:1) to afford 8 mg (4.8%) of the title compound as white solids: MS (ESI) m/z 491 [M+H]+, 489 [M−H]−, 1H-NMR (CDCl3) δ 2.27 (s, 3H), 2.87 (2H, t, J=5.9 Hz), 3.50 (3H, s), 4.24 (2H, t, J=5.7 Hz), 7.56-7.15 (11H, m), 7.83-7.80 (2H, m).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:44])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][C:32]=2[OH:43])[CH2:28]O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[C:13]([O:17][C:18](=[O:44])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]2[CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=4)[N:34]=[CH:33][C:32]=3[O:43][CH2:28]2)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc2ncc(O)c(CC(CO)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (455 μL, 2.90 mmol, 3.0 eq) is added at 0° C. to a stirred solution of {trans-4-[3-hydroxy-2-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (430 mg, 0.97 mmol, 1.0 eq) in tetrahydrofuran (100 mL), followed by triphenylphosphine (761 mg, 2.90 mmol, 3.0 eq). After 2 hours stirring at room temperature, solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as an off-white solid (247 mg, 60% yield).