Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C:15]1(CC(O)=O)CCCCC1.CC#N.O.CC#N>O>[C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Reactant: NC1(CC(=O)O)CCCCC1
Solvent: O
Solvent: CC#N
Product: CC(=O)NC1(CC(=O)O)CCCCC1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (1-amino-cyclohexyl)-acetic acid. MS (LC-MS): [M+H]+=200.1. (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.81 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=4)[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(C(F)(F)F)c3)CC12
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-(trifluoromethyl)phenylacetic acid (1.43 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-(trifluoromethyl)phenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 184° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:26]4[CH:27]=[CH:28][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([O:16][CH3:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:24][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 20.3 %

Procedure:
To a solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.19 mmol, Preparation 27) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) dissolved in toluene (1.18 mL) and water (0.43 mL) was added potassium carbonate (127 mg, 0.92 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (13.55 mg, 0.017 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored solid, which was purified by silica gel chromatography (12 g silica, EtOAc/hexanes 40 to 100%) to produce the title intermediate (35.3 mg, 21% yield) as a yellowish colored solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O8 913.35. found 913.3.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:27])([F:1])[F:26])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2)N1CCC(O)CC1

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 4-hydroxypiperidine gave 129. MS: (ESI+)=463.1. 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=2.0 Hz, 1H), 8.09 (d, J=4.4 Hz, 2H), 7.37 (dd, J=8.4, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.87 (q, J=8.5 Hz, 2H), 4.76 (d, J=3.8 Hz, 1H), 4.57 (s, 4H), 3.76 (d, J=3.6 Hz, 2H), 1.74 (s, 2H), 1.39 (s, 2H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]([CH3:21])[CH2:19][C:18](=[O:22])[NH:17][N:16]=2)=[CH:11][CH:10]=1.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:21][C:20]1[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[NH:5][N:4]=3)=[CH:14][CH:13]=2)=[N:16][NH:17][C:18](=[O:22])[CH:19]=1
Reactant: CC1CC(=O)NN=C1c1ccc(C2=NNC(=O)CC2C)cc1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)[nH]nc1-c1ccc(-c2n[nH]c(=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A mixture of 1,4-bis(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzene (1.41 g), sodium m-nitrobenzenesulphonate (2.20 g) and sodium hydroxide (1 g) in water (100 ml) was stirred under reflux until a clear solution was obtained. Stirring under reflux was continued for one hour and the reaction mixture was cooled to room temperature and filtered. The filtrate was acidified with acetic acid to give a white precipitate, which could not be collected by filtration as it passed through the sinter funnel. The mixture was basified with sodium hydroxide to pH 14 and the resulting solution was then taken to pH 10 with aqueous sodium bicarbonate and allowed to stand at room temperature for 16 hours. A pale yellow solid was collected and was dissolved in dilute aqueous sodium hydroxide. The solution was taken to pH 11 with saturated aqueous ammonium chloride to afford 1,4-bis(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzene (1.02 g), m.p.>250° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH3:33][O:32][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCN3CCOCC3)c(OC)cc12
Temperature: 60 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
Propyl 3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 322) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (484 mg) and morpholine (0.15 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (52 mg, yield 59%).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.I[CH:19]([CH3:21])[CH3:20].C[Si](C)(C)N[Si](C)(C)C.[Li]>C1COCC1>[CH:19]([C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)([CH3:21])[CH3:20]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (0.55 g, 2.26 mmol) and 2-iodopropane (0.32 mL, 3.2 mmol) in THF (2.5 mL) was stirred at −78° C. Lithium hexamethyldisilazane (3.2 mL, 3.2 mmol) was added, then the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was partitioned between diethyl ether and brine. The ether extract was dried (MgSO4), filtered and concentrated in vacuo, to give the title compound (0.54 g, 84%) as a pale yellow syrup, which was used without further purification. δH (400 MHz, DMSO-d6) 3.86 (m, 2H), 3.68 (m, 3H), 2.69 (m, 2H), 1.99 (m, 2H), 1.68 (m, 1H), 1.53 (m, 1H), 1.36 (s, 9H), 1.28 (m, 1H), 0.80 (d, J 6.9 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[C:18]3[C:23](=[O:24])[O:22]C(C)(C)OC3=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:28]([Mg]Br)#[C:29][CH3:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:28]#[C:29][CH3:30])[CH2:18][C:23]([OH:22])=[O:24])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CC#C[Mg]Br
Reactant: COc1ccc(COc2ccc(C=C3C(=O)OC(C)(C)OC3=O)cc2)cc1
Solvent: C1CCOC1
Product: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a stirring THF (120 mL) solution of compound 12.2 (13.8 g, 37.5 mmol) under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water, dried over MgSO4, filtered, and concentrated to a brown oil. A solution of this brown oil in 5:1 pyridine-water (360 mL) was heated at 100° C. for 36 h. The reaction mixture was cooled to room temperature and put in an ice-water bath. Concentrated HCl was carefully added to pH ˜2. The resulting suspension was extracted with ethyl acetate (200 mL×3), dried over MgSO4, filtered, and concentrated to an off-white solid. Recrystalization from ethanol gave 9.5 g (78%) of compound 12 as a white powder. 1H NMR (500 MHz) DMSO-d6) δ 12.2 (s, 1H); 7.37 (d, 2H, J=8.5 Hz); 7.27 (d, 2H, J=8.5 Hz); 6.95 (d, 2H, J=8.0 Hz); 6.94 (d, 2H, J=8.5 Hz); 4.99 (s, 2H); 3.95 (m, 1H); 3.76 (s, 3H); 2.60 (m, 2H); 1.78 (d, 3H, J=1.5 Hz). MS ESI (neg.) m/e: 323.0 (M−1).
Reaction SMILES: C(#N)C.FC(F)(F)C(O)=O.[Br:11][C:12]1[C:13]([OH:18])=[N:14][CH:15]=[CH:16][CH:17]=1.[I:19]N1C(=O)CCC1=O>O>[Br:11][C:12]1[C:13]([OH:18])=[N:14][CH:15]=[C:16]([I:19])[CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1Br
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Oc1ncc(I)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 190.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (50 mL), trifluoroacetic acid (10 mL), 3-bromopyridin-2-ol (4.0 g, 11.56 mmol) and N-iodosuccinimide (5.2 g, 11.56 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (100 mL) and resulting white solid was collected by filtration to afford 214a (6.6 g, 96%) as a white solid. MS-ESI: [M+H]+ 300
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N[C@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 216°-219° C.
Reaction SMILES: C(N1CCCCC1)C.C(O)=O.CC1(C)[O:20][C:18](=[O:19])[CH2:17][C:15](=O)O1.C(=O)[C:23]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[C:25]([O:26][CH3:27])[CH:24]=1>>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH2:15][CH2:17][C:18]([OH:20])=[O:19])[CH:32]=[CH:31][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN1CCCCC1
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 95 °C

Procedure:
After dropwise adding 27.2 g (33.1 ml, 0.24 mol) of 1-ethylpiperidine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the solution which was then heated to 95° C. during 1 hour and reacted at the same temperature for 2 hours. Subsequently the method of Example 1 was followed.
Reaction SMILES: CN1CCCC1=O.[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1Cl)[C:9]#[C:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[N:33]1[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 130 °C
Yield: 99.2 %

Procedure:
5 ml of 1-methyl-2-pyrrolidone was added to a mixture consisting of 1.183 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 0.829 g of potassium carbonate, and 1.395 g of t-butyl piperazine-1-carboxylate under a nitrogen atmosphere. The resulting mixture was heated at 130° C. for 6 hours. The reaction mixture was cooled, and 50 ml of water was added thereto. Then, the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Thus, 1.916 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:31])=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45]Cl.[I-].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:31][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)CC2
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OCCN(C)C)cc3C2)Sc2ccc(C)cc2)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 0.583 g of α-(3,4-dimethoxyphenyl)-3,4-dihydro-7-hydroxy-6-methoxy-α-[(4-methylphenyl)thio]-2(1H)-isoquinolineheptanenitrile in 20 mL of N,N-dimethylformamide is added 0.051 g of 60% sodium hydride in oil and the solution stirred for 1 hour. To this solution is added 0.34 g of freshly prepared 2-dimethylaminoethylchloride and 0.60 g of potassium iodide. The solution is stirred at room temperature for 18 hours and then the volatiles are removed at reduced pressure. The residue is dissolved in a minimum amount of ethyl acetate and 5 volumes of diethyl ether is added. This solution is passed through a short pad of hydrous magnesium silicate and the volatiles are removed at reduced pressure. The residue is chromatographed on silica gel using a gradient of diethyl ether to ethyl acetate to methyl alcohol. This afford 0.14 g of the desired product as a clear glass.
Reaction SMILES: [C:1]([C:8]1[C:9]([NH:19][CH3:20])=[C:10]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:22][OH:23]>>[C:1]([C:8]1[C:9]([NH:19][CH3:20])=[C:10]([C:14](=[N:22][OH:23])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CNc1c(C(=O)OC(C)(C)C)cccc1C(=O)C(=O)O
Reactant: NO
Agent: Cl
Product: CNc1c(C(=O)OC(C)(C)C)cccc1C(=NO)C(=O)O

Procedure:
32.2 g of 2-(3-BOC-methylaminophenyl)-glyoxylic acid are reacted with 13.8 g of hydroxylamine hydrochloride in the manner described in Example 4. Crystallisation from CH2Cl2 /CH3OH/ether/hexane yields 2-(3-BOC-methylaminophenyl)-2-hydroxyiminoacetic acid. M.p. 135° (decomposition). IR: 3620, 3600-2300 (wide), 1688, 1600, 1590 (shoulder) cm-1 (CH2Cl2).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CS(OS(C)(=O)=O)(=O)=O.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:37][CH2:38][CH3:39])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:18][C:17]=2[N:16]=1.CO>ClCCl>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:37][CH2:38][CH3:39])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:3])[CH3:2])=[CH:18][C:17]=2[N:16]=1
Reactant: CC(=O)Cl
Reactant: CCCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CCCCNS(C)(=O)=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CCCCNS(C)(=O)=O
Yield: 33.1 %

Procedure:
A modification of the method described in Park K of Example 45 was followed using acetyl chloride (135 μL, 1.91 mmol) in lieu of methanesulfonic anhydride and N-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide (0.85 g, 1.7 mmol) as the starting material. The crude product was purified by column chromatography on silica gel (eluting sequentially with 90:10 and 80:20 dichloromethane:methanol). The resulting white powder was stirred with water, isolated by filtration, and dissolved in 50:50 dichloromethane:methanol. The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and further dried overnight under high vacuum at 60° C. to provide 0.30 g of N-(6-{4-amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy}hexyl)acetamide as a white powder, mp 168-172° C.
Reaction SMILES: [C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O-:17])=[O:16])#[N:2].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>C(OCC)(=O)C>[C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])#[N:2]
Reactant: CC(C)C1(C)N=C(c2ncccc2C(=O)[O-])N(C#N)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)C1(C)N=C(c2ncccc2C(=O)O)N(C#N)C1=O
Yield: 42 %

Procedure:
Tetrabutylammonium 2-(1-cyano-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.36 g, 0.00068 mol) is placed into a mixture of cyclohexane and ethyl acetate for 3 months. The mixture is filtered to yield the title compound as a tan solid (0 09 g 42%) mp 150°-153° C. identified by IR and NMR spectral analyses.
Reaction SMILES: [ClH:1].[F:2][CH2:3][CH:4]([NH:18]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH:7]([NH:10]C(OC(C)(C)C)=O)[C:8]#[CH:9]>CCOCC>[ClH:1].[ClH:1].[F:2][CH2:3][CH:4]([NH2:18])[CH2:5][CH2:6][CH:7]([NH2:10])[C:8]#[CH:9]
Reactant: C#CC(CCC(CF)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C#CC(N)CCC(N)CF
Reaction time: 8 h

Procedure:
A saturated solution of dry hydrogen chloride in dry ether (10 ml) is added to 1-fluoro-2,5-di-(N-tert.butoxycarbonylamino)-6-heptyne obtained as in Step D above (1 mmole) and left overnight at room temperature. The dichlorohydride which forms as crystals is filtered, washed with ether, and dried to give the title compound (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH2:13][N+:14]=1[O-].[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:26][CH:13]1[C:12](=[O:16])[N:11]([CH3:17])[C:10]2=[CH:18][N:19]([CH3:22])[C:20]([CH3:21])=[C:9]2[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:14]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2c(cn1C)N(C)C(=O)C[N+]([O-])=C2c1ccccc1Cl
Product: CC(=O)OC1N=C(c2ccccc2Cl)c2c(cn(C)c2C)N(C)C1=O
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
The compound obtained in step (d) above was suspended in acetic anhydride (660 ml) and the reaction flask was heated in a water-bath at 55° C. After stirring for 15 minutes the reaction mixture was concentrated to dryness under vacuum, and the obtained residue was taken up with boiling ethanol and treated with charcoal. By concentrating to a volume of 600 ml and cooling, the compound of the title (103 g) crystallized. M.p. 202°-4° C.