Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]1([CH:17]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:17](=[C:9]1[C:10]2[N:1]=[C:2]([CH:3]=[CH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=Cc1ccccc1
Product: C(=Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2)c1ccccc1
Temperature: 165 °C
Yield: 197.8 %

Procedure:
A 1 L round-bottomed flask equipped with a stirring bar, condenser and nitrogen gas inlet was charged with 2-methyl-5,6,7,8-tetrahydroquinoline (2, 80.5 g, 0.547 mol), PhCHO (222 mL, 2.19 mol), and Ac20 (206 mL, 2.19 mol). The mixture was heated under reflux at 160-170° C. under nitrogen atmosphere for 5 days. Then all volatile materials were removed by distillation under atmospheric pressure at ˜170° C. The residue was mixed with hot EtOH (200 mL) and stirred at 70° C. The stirred solution was cooled to room temperature and seeded with crystals of the product 3 to facilitate crystallization. The precipitate was collected by vacuum filtration, washed with EtOH (100 mL) and dried in vacuo to give the pale brown solid (175 g), which was impure. The crude material was chromatographed over silica gel (hexane only) to give bisbenzylidene 3 (142.4 g, 83%) as a pale yellow solid. Physical data see A. B. Khasanov's Ph. D. Thesis (2000).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.CON(C)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Reactant: CON(C)C(=O)C(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(=O)Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: -40 °C

Procedure:
Following the procedure described by R. D. Clark et al. in Synthesis, 871 (1991), (4-chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (2.18 g, 9 mmole) was dissolved in anhydrous THF (30 ml) and cooled to −40° C. and s-BuLi (14.56 ml 1.3N in cyclohexane) was added slowly at such a rate to maintain the temperature below −25° C. The bright yellow solution was cooled to −50° C. and a solution of N-methoxy-N-methyl-isobutyramide (1.24 g, 9.5 mmole) in THF (5 ml) was added. The mixture was allowed to warm up to −10° C. over a 20 m period during which time the solution turned nearly colorless. Ether (50 ml) was added and the solution was poured into 1% aqueous HCl (50 ml). The aqueous layer was extracted a second time with ether (30 ml) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1) to afford pure [4-chloro-2-(3-methyl-2-oxo-butyl)-phenyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@H:23]([C:31]3[N:35](CCC#N)[N:34]=[N:33][N:32]=3)[C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1CCN2C(=NCCC2)CC1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@H:23]([C:31]3[NH:35][N:34]=[N:33][N:32]=3)[C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(C[C@@H](c3cccc(C)c3)c3nnnn3CCC#N)cc2-c2ccc(Cl)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-n2nc(C[C@@H](c3cccc(C)c3)c3nnn[nH]3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a solution of 3-(5-{(S)-2-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-tetrazol-1-yl)-propionitrile (1.5 g, 2.7 mmol) in dichloromethane (25 mL) was added DBU (2.9 mL, 18.9 mmol, 7.0 equiv), and the mixture was stirred at room temperature for 48 h. Dichloromethane (200 mL) was added, and the resulting mixture was washed with 1 N HCl (2×100 mL) then water (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (50% dichloromethane/ethyl acetate) to afford the title compound (1.3 grams, 95%). HPLC: Rt=5.31 (Method A). MS (ESI): mass calculated for C26H22Cl2N6O, 504.12; m/z found, 505.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 3H), 7.21 (t, J=7.7 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.08 (d, J=7.7 Hz, 1H), 6.95-6.94 (m, 3H), 6.88 (dd, J=8.5, 2.2 Hz, 1H), 6.18 (s, 1H), 4.85 (dd, J=9.0, 3.6 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, J=14.8, 8.5 Hz, 1H), 3.42 (dd, J=15.4, 3.6 Hz, 1H), 2.31 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH2:31]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COc2cccc3c2CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3c(cccc3OCc3ccccc3)C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A suspension of 0.098 g (0.00051 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 2 ml of dimethylformamide was treated with 0.21 ml (0.0015 mol) of triethylamine and 0.145 g (0.00061 mol) of 5-benzyloxy-1,2,3,4-tetrahydro-isoquinoline (WO 94/20459) and the mixture was stirred at room temperature under argon for 18 hours The solvent was distilled off in a high vacuum. The residue was partitioned between dichloro-methane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.153 g (84%) of 5-(5-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a yellowish oil. MS (ISP): me/e=361 (C22 H25N4O+).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[CH:8][CH:7]=1>CS(C)=O.CN(C=O)C>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=2)=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (0.75 g) was added to a solution of the crude product from step (vi) in DMSO (10 ml) and DMF (10 ml). The mixture was stirred at rt for 18 h, then partitioned between EtOAc/water. The organics were separated, washed with aq NaHCO3 solution, dried and evaporated under reduced pressure to afford the subtitle compound, 1.2 g.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)=[O:6].[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:23]([OH:24])[CH2:22]1>O1CCOCC1>[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([OH:4])=[O:6])=[CH:8][CH:9]=2)[CH2:22]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
Potassium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide was added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of water and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was rendered acidic with acetic acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The concentrate was dissolved in 50 ml of a 80% aqueous solution of acetic acid. The solution was heated to 100° C. for 2 hours. The solvent was distilled off and the residue was applied to silica gel column chromatography using 3% methanol-chloroform as an eluent, affording 650 mg of the title compound in a yield of 28%.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH2:15][CH3:16])[CH:6]=1)#[N:4]>CCO>[NH2:4]/[C:3](=[N:1]/[OH:2])/[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH2:15][CH3:16])[CH:6]=1
Reactant: CCc1cc(C#N)ccc1NC(C)=O
Reactant: NO
Solvent: CCO
Product: CCc1cc(/C(N)=N\O)ccc1NC(C)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Hydroxylamine (5.95 g, 90.0 mmol, 50 wt. % aq. solution) was added to a stirred solution of N-(4-cyano-2-ethylphenyl)acetamide (5.65 g, 30.0 mmol) in EtOH (70 mL), and the resulting mixture was heated to 90° C. After 2 h, the reaction mixture was cooled to rt and concentrated in vacuo to afford the title compound i-5a. m/z (ES) 222 (MH)+
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Fe]>[CH:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12](=[O:14])[CH2:11][CH2:10][CH:7]2[CH2:6][CH2:5][CH:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCC(CCC(=O)O)CC1
Agent: [Fe]
Product: CC(C)C1CCC(CCC(=O)CCC2CCC(C(C)C)CC2)CC1
Temperature: 290 °C

Procedure:
3-(4-Isopropylcyclohexyl)propionic acid (39.7 g., 0.20 mole) and iron (hydrogen reduced, 6.15 g., 0.11 mole) is heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for 3 hours. The cooled reaction mass is extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under vacuum to leave the product, 17.3 g. (51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:27][CH3:28])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CCN(CC)CC>[CH3:28][O:27][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline [Example 1c] (9.2 g, 0.024 mol) and 4-bromo-1-phthalimidopentane (BPP) (15 g, 0.05 mol) was heated at 120°-125° C. while Et3N (5 ml) was added in small portions. After 3 h at 120°-125° C., second portions of BPP (7.5g) and Et3N (2.5 ml) were added and heating was continued for 4 h. Third portions of BPP (3 g) and Et3N (1 ml) were introduced, and heating was continued for 2 h. The reaction was allowed to cool and extracted with Et2O (total, ca. 500 ml). The extract was treated with carbon and then with saturated ethereal hydrogen chloride (300 ml). The resulting dark red semi-solid mass was separated and basified with Et2O - Et3N. Concentration of the ethereal solution left 11.5 g (81%) of brown oil which was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. The first six eluates (75 ml each) were combined and concentrated to give 10.9 grams of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(7-phenylheptoxy) quinoline which was used without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[C:12]([O:16][C:17](=[O:20])[CH2:18]Br)([CH3:15])([CH3:14])[CH3:13].Cl>C(O)C>[C:12]([O:16][C:17]([CH2:18][S:8][C:5]([CH3:7])([CH3:6])[C@H:4]([NH:3][C:17]([O:16][CH2:12][CH3:13])=[O:20])[C:9]([OH:11])=[O:10])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (0.81 g; 35.2 mmol) was added in portions to 40 mL ethanol while cooling. Subsequently D-penicillamine (2.50 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which bromoacetic acid tert.-butyl ester (2.55 mL) was added. The mixture was allowed to stir 16 h at ambient temperature and subsequently hydrolyzed with 2 N HCl. The solvents were distilled off, the residue was redissolved in 50 mL of water and 50 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (2.1 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 10) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a colorless oil, which was purified by HPLC (RP-18; pH 2.3, H2O/CH3OH 3/7) to give 0.86 g (15%) of the title compound as a colorless oil. (+)-APCI-MS: 358 (MNa+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:40](F)[CH:39]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]>CS(C)=O.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:39]=[CH:40][C:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[C:49]([NH:16][CH:11]5[CH2:10][CH:9]6[N:8]([CH3:7])[CH:13]([CH2:14][CH2:15]6)[CH2:12]5)[CH:50]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: CN1C2CCC1CC(N)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Yield: 27 %

Procedure:
0.89 g of potassium carbonate and 6 g of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 100° C. for 1 hour and 40 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (92/8 as mixtures), so as to give 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].I[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]4)=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Product: CCCc1nc2cnc3cc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)C

Procedure:
The general method described in Part L of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. After the work-up procedure, tert-butyl 4-(2-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate was isolated as a gray-brown solid and used without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14](O)=O)[CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)CO.O>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:10]1[CH2:9][N:8]([CH2:13][C:14]1[NH:24][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: c1ccc(CN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 4.00 g (17.9 mmol) N-benzyliminodiacetic acid and 3.86 g (35.8 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3×30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 4.94 g (75.0%). 1H NMR (250 MHz, DMSO-d6), δ 3.72 (s, 2H), 3.92 (s, 4H), 7.13–7.57 (m, 13H), 12.37 (Br. s, 2H). +CI MS (m/z): [368]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([NH:12]C(=O)C)[CH2:4][CH2:3]1.[ClH:16]>>[ClH:16].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: CC(=O)N[C@H]1CCC(=O)c2ccccc21
Agent: Cl
Product: N[C@H]1CCC(=O)c2ccccc21
Reaction time: 24 h

Procedure:
A 20 g. sample of (S)-N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide is stirred with 600 ml. of 6N HCl and the mixture is heated to flux for 24 hours. After allowing to stand for 48 hours, the aqueous solution is decanted and the remaining tar is washed with 200 ml. of H2O. The combined aqueous solutions are washed with CHCl3 (3×200 ml.) and the organic washes are counter-washed with 200 ml. of H2O. The combined aqueous solutions are filtered through celite and the filter cake is washed with 50 ml. of H2O. The aqueous filtrates are then evaporated to dryness in vacuo to afford the title compound, m.p. 230° C. to 235° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:25])[C:18]3=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][C:20]([NH:23][C:35]3[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=3)=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:25])[C:18]3=[O:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc(N)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc(Nc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a suspension of 4-(7-Amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.14 g, 18 mmol) and potassium carbonate (3.86 g, 4.76 mmol) in dimethylsulfoxide (60 mL), 2,4,5-trichloropyrimidine (3.1 mL, 27 mmol) is added and the mixture is stirred at 60° C. for 2 hours. To the mixture, 2,4,5-trichloro pyrimidine (1.0 mL, 9 mmol) is added. After stirring at 60° C. for 2 hours, 2,4,5-trichloropyrimidine (1.0 mL, 9 mmol) is added and the mixture is further allowed to stir at 60° C. for 10 hours. The mixture is cooled and then poured into iced water. The resulting brown solids are collected by filtration and washed with MeOH, and dried in vacuo at 50° C. to afford 4-[7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as brown solids (5.29 g) in 60% yield. Rf=0.28 (Hexane/AcOEt=111). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.50 (s, 9H), 2.99 (t, 4H), 3.23 (s, 3H), 3.59 (t, 4H), 4.40 (s, 2H), 7.18 (d, 1H), 8.21 (s, 1H), 8.67 (d, 1H), 11.0 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH:9]1[CH:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH:13]2[CH2:19][CH:10]1[CH2:11][CH2:12]2)[CH3:8])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]([CH:9]1[CH:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]2[CH2:19][CH:10]1[CH2:11][CH2:12]2)[CH3:8])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(C)C1C2CCC(C2)C1C=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)C1C2CCC(C2)C1CC(C)C
Reaction time: 5 h

Procedure:
A solution of 60 g (0.22 mole) of 2-(1-ethoxycarbonylprop-1-en-2-yl)-3-(2-methylprop-1-en-1-yl)-bicyclo[2.2.1]heptane in 100 ml of ethyl acetate was stirred together with 1.6 g of palladium on alumina (0.5% strength) at 90° C. in a hydrogen atmosphere under 150 bar until the pressure remained constant for 5 hours.