Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45](Cl)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43])(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Reactant: CCOC(=O)C1CCCCN1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidine carboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:37][C:38]1[N:43]=[C:42]([N:44]([CH3:46])[CH3:45])[CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([N:44]([CH3:46])[CH3:45])[N:43]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CN(C)c1cccc(CCl)n1
Product: COc1ccc(N(Cc2cnn(Cc3cccc(N(C)C)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 25.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.68 g) as starting materials, 5-benzyloxy-N-({1-[(6-(dimethylamino)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. 1H-NMR (CDCl3) δ: 1.38-1.67 (1H, m), 1.73-2.07 (3H, m), 2.61-2.82 (2H, m), 3.04 (6H, s), 3.59-3.72 (1H, m), 3.93 (3H, s), 4.64 (1H, d, J=14.4 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.21 (2H, s), 6.18 (1H, d, J=7.2 Hz), 6.40 (1H, d, J=8.4 Hz), 6.54 (1H, d, J=7.5 Hz), 6.62-6.76 (2H, m), 7.01 (1H, t, J=8.0 Hz), 7.21-7.52 (9H, m), 7.99 (1H, d, J=2.4 Hz).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1>>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][NH:3][CH2:1][CH3:2]
Reactant: BrCc1cccc(Br)c1
Reactant: CCN
Solvent: CO
Product: CCNCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To 80% ethylamine/MeOH (1.1 g) was added 1-bromo-3-(bromomethyl)benzene (1 g) in five divided portions at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid separation with chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica, 3% MeOH/CHCl3) to obtain N-(3-bromobenzyl)ethanamine (610 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:13][C:3]1[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:6]2[C:8]([NH2:11])=[N:9][N:10]=[C:5]2[C:4]=1[CH3:12]
Reactant: C1CCNC1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Solvent: O
Product: Cc1c(N2CCCC2)nn2c(N)nnc2c1C
Temperature: 65 °C

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 500 mg) were initially charged in pyrrolidine (5 ml) at RT while stirring. Then the mixture was heated to 65° C. for 4 h. Thereafter, the pyrrolidine was drawn off, and the residue was taken up with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 438 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:10]1[C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c(Cl)cccc2c(=O)o1
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (4.93 g, 28.7 mmol) in acetic anhydride (15 mL) was refluxed for 3 h, then cooled to room temperature. The precipitated solid was filtered, and washed with hexane. The title compound was obtained as a brown solid (4.33 g). 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 2.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:19]2[N:14]([CH:15]=[CH:16][C:17](=O)[CH:18]=2)[CH2:13][CH:12]=1>>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=c1ccn2c(c1)C=CC2
Product: Fc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-fluoro-1H-indole (910 mg, 6.7 mmol) and 7-indolizinone (1.40 g, 10.1 mmol) were converted to product by the procedure of Example 2 to give 1.22 g. (70.9%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (68 mg, 0.3555 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 64% yield (0.109 g, 0.1893 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[CH2:32](Br)[CH3:33]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][CH2:32][CH3:33])=[C:3]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CCBr
Product: CCNc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the procedure described in Example 39, the product of Example 17 was reacted with one equivalent of ethyl bromide to afford the title compound. HPLC/MS: 500.9 (M+1), 502.9 (M+3); Rt=4.08 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:25]1[O:26][C:27]2[CH:28]=[CH:29][C:21]([CH2:20][NH:30][C:2]3[N:11]=[C:10]([O:12][CH3:13])[C:9]4[C:4](=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=4)[N:3]=3)=[CH:22][C:23]=2[O:24]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1cc2c(OC)nc(Cl)nc2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc2c(OC)nc(NCc3ccc4c(c3)OCO4)nc2c(OC)c1OC
Yield: 8.6 %

Procedure:
1.00 g (3.51 mmol) of 2-chloro-4,6,7,8-tetramethoxyquinazoline, 0.60 g (3.97 mmol) of piperonylamine and 0.60 g of sodium carbonate were mixed with 30 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.12 g of the title compound as an oily substance.
Reaction SMILES: Cl.CN[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][CH3:13])[C:6]=1[OH:14].C1C[O:19]CC1>O.CC(OC)(C)C>[CH3:13][NH:12][C:11](=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]=[O:15])[C:6]=1[OH:14]
Reactant: CN=Cc1cccc(C(=O)NC)c1O
Reactant: C1CCOC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CNC(=O)c1cccc(C=O)c1O
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
60 ml of concentrated aqueous hydrochloric acid were added at 20 to 25° C. to 14 g (65 mmol) of the methylamide of Example 3 in a mixture of 120 ml of THF and 100 ml of water. After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was taken up in MTBE and washed with water. After drying, the solvent was distilled off. 8 g of the title compound, which corresponded to 71% of theory, were obtained from the residue. (m.p.: 129-131° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:27]1([C:25]([C:15]2[CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=[C:13]([NH:12][C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)[CH:14]=2)=[O:26])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Nc1cc(C(=O)N2CCOCC2)cc(-c2ccccc2)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccccc2)c1)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (34 mg, 0.186 mmol), (5-aminobiphenyl-3-yl)(morpholin-4-yl)methanone (63.1 mg, 0.224 mmol), sodium tert-butoxide, Pd2(dba)3 (9.64 mg, 0.009 mmol) and BINAP (11.6 mg, 0.019 mmol) in toluene (0.931 mL) was heated to 130° C. in a microwave reactor for 30 minutes, then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and was washed with 0.1 M HCl (30 mL) followed by brine (30 mL). The aqueous phases were further extracted with ethyl acetate (30 mL), then the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided morpholin-4-yl(5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)methanone as a white solid. MS ESI calc'd. for C22H20F3N4O2 [M+H]+ 429, found 429. 1H NMR (400 MHz, CDCl3): δ 8.69 (d, J=4.9 Hz, 1H); 7.92 (s, 1H); 7.80 (s, 1H); 7.71 (s, 1H); 7.63 (d, J=7.6 Hz, 2H); 7.48 (t, J=7.5 Hz, 2H); 7.40 (d, J=6.8 Hz, 2H); 7.15-7.03 (m, 1H); 3.97-3.44 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:3]2[CH2:4][NH:5][CH2:6][CH2:7][N:2]2[CH3:1])=[CH:13][C:12]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1nc2ccccc2o1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCNCC1c1ccc([N+](=O)[O-])c(-c2nc3ccccc3o2)c1
Temperature: 90 °C

Procedure:
1.01 g (0.010 mol) of N-methylpiperazine were added to the mixture of 1.29 g (0.005 mol) of 2-(2′-nitro-5′-fluorophenyl)benzoxazole and 1.04 g (0.0075 mol) of K2CO3 in 9 ml of dimethyl sulfoxide. The reaction was stirred magnetically and heated at 90° C., the progression thereof being verified by TLC.
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)C.[Cl-].[Na+]>O1CCCC1>[OH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1[nH]c2cccc3c2c1CCC3=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cccc3c2c1CCC3O
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 1,3,4,5-tetrahydro-5-oxo-benz[cd]indole-2-carboxylate (0.40 g, 1.64 mmol), sodium borohydride (0.062 g, 1.64 mmol), ethanol (2 ml) and tetrahydrofuran (8 ml) was stirred at 0°-5° C. for 1.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution, followed by extraction with ethyl acetate (three times). The extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=15/85) to obtain ethyl 1,3,4,5-tetrahydro-5-hydroxy-benz[cd]indole-2-carboxylate (0.40 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30](O)=[O:31])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:31])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)C1C3CC4CC(C3)CC1C4)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.096 ml was added to a methylene chloride 5 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg and stirred at O@C for 30 min. 2-adamantane carboxylic acid 0.11 g and WSC 0.13 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 17 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(2-adamantylcarbonyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 24.0 mg and refluxed under heating for 2 hours. The-reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:25])[NH:21][N+]([O-])=O)=[O:13])[CH3:11])=[O:8].CO.Cl>[Pd].O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:25])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 6 h
Yield: 50.8 %

Procedure:
After 1.75 g (2.6 mmols) of Z-PyroGlu-Ala-Arg(NO2)-CHA was suspended in a solvent mixture of 112.5 ml of MeOH, 27.7 ml of H2O and 9.8 ml of 1N-HCl, 1 g of palladium black was added to the suspension followed by catalytic reduction at 30° C. for 6 hours. After the reaction, the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was purified through TOYOPEARL HW40F column using MeOH as a developing solvent to give 0.471 g (34.4%) of H-PyroGlu-Ala-Arg-CHA.HCl.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]#[N:25])=[CH:16][CH:15]=2)[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]#[N:25])=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:36][CH3:37])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)c2ccccc12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)c3ccccc13)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
93 mg (0.262 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-1-naphthonitrile are dissolved under an argon atmosphere in 5 ml of abs. dichloromethane, and 99.4 mg (0.268 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 60 mg (59.8% of theory) of the title compound are obtained.
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.[OH-:22].[Na+]>O>[OH:22][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: [OH-]
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Agent: Br
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
50 g (0.118 mol of 3(R,S)-bromo-1-methyl4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) were heated under reflux for 2 h in 100 ml of water. The reaction mixture was then cooled to 20° C. and adjusted to pH 12.5 by dropwise addition of 30 ml of 30% strength sodium hydroxide solution. After a short time, a pale brown precipitate crystallized out. The mixture was stirred at 5-10° C. for a further 1 h, and the precipitated product was filtered off with suction and washed with 30 ml of water. The crude product was then stirred with 20 ml of acetone, filtered off with suction and dried in vacuo.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(O)c2)CC1
Yield: 13.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.96 g) as a starting compound, 6-bromo-1-(3-hydroxyphenyl)-1-hexanone (0.70 g) and potassium carbonate (1.60 g) were reacted and purified in the same manner as in Example 172 to give 0.17 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-hydroxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].C([O-])(=O)CC([O-])=O.Br[CH2:24][C:25]([O:30][CH3:31])([O:28][CH3:29])[CH2:26]Br.[Cl-].[NH4+]>CN(C=O)C>[CH:13]([O:12][C:3]([C:4]1([C:5]([O:7][CH:8]([CH3:9])[CH3:10])=[O:6])[CH2:26][C:25]([O:30][CH3:31])([O:28][CH3:29])[CH2:24]1)=[O:11])([CH3:15])[CH3:14]
Reactant: COC(CBr)(CBr)OC
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A 1 L, two-necked flask containing 95% NaH (5.04 g, 210 mmol) was charged with 75 mL of DMF, evacuated, placed under a nitrogen atm, and cooled in an ice bath. Diisopropyl malonate (34.0 mL, 191 mmol) was carefully added dropwise via addition funnel under a positive flow of nitrogen (reaction vented through a needle placed in a septum on the second neck of the flask). After the addition of the malonate, the solution became very thick and yellow in color. After stirring for 1 h, the reaction was charged with 1,3-dibromo-2,2-dimethoxypropane (25.0 g, 95.4 mmol) in one portion and the reaction was heated to 140° C. for 24 h, upon which time the reaction became thick and orange in color. Saturated ammonium chloride (300 mL) was added and the mixture was extracted with hexanes (3×, 500 mL). The organic layers were combined, washed with water (2×, 500 mL), saturated bicarbonate (2×, 500 mL), water (2×, 500 mL), and brine (1×, 500 mL), then dried over Na2SO4, filtered and concentrated to an oil. Short path distillation (4-5 torr, oil bath temperature at 60° C. to 143° C.) afforded the title compound as a clear oil; 1H NMR (400 MHz, CDCl3) δ 1.24 (d, 12H, J=6.0 Hz), 2.70 (s, 4H), 3.15 (s, 6H), 5.06 (m, 2H).