Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccncc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:36][C:23]([F:35])([C:24]1([OH:34])[CH2:25][C:26]([CH3:32])([CH3:33])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][N:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]2=[O:44])[O:16][N:15]=1)=[O:37]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(Cn3ccccc3=O)on2)C1
Temperature: 50 °C
Yield: 53.4 %

Procedure:
To a DMF (1.0 mL) solution of the compound (30 mg) obtained in Example 3-(5) and pyridin-2-ol (12 mg), K2CO3 (35 mg) was added and the mixture was stirred at 50° C. for an hour. To the reaction mixture, DMSO (1.0 ml) was added and after filtering off the insoluble matter, the filtrate was purified by reverse-phase preparative HPLC to give Compound 54 (2.0 mg, colorless oil) and Compound 60 (16.0 mg, colorless oil.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:20][C:19]=3[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]2)[CH:4]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nn(-c2cc(N)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.6 %

Procedure:
A stirred solution of 200 mg (0.303 mmol) of 2-(2-bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) in 3.5 mL of THF was cooled to 0° C. and treated dropwise with a solution of 542 mg (2.4 mmol) of stannous chloride dihydrate in 1.5 mL of concentrated hydrochloric acid. After 45 minutes, the mixture was added to a vigorously stirred mixture of 50% NaOH and ice. Ethyl acetate (15 mL) was added, and the mixture was stirred at 0° C. for 1.5 hours. The phases were separated, and the aqueous fraction was re-extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine and dried over anhydrous Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed on silica gel to give 131 mg (68%) of the title compound as a stiff, off-white foam, mp 103°-105° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 629, 631 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[NH:19][C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41]CC)=[O:40]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:38][C:39]([OH:41])=[O:40])[C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-Methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (70 mg) and potassium carbonate (28 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and ethyl bromoacetate (22 μl) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated by distillation, and ethanol (1.5 ml) and 2 N sodium hydroxide aqueous solution (0.5 ml) were added to the resulting residue. The reaction mixture was stirred at room temperature for 3 hours, diluted with water, and neutralized with 2 N hydrochloric acid. After the mixture was extracted with ethyl acetate, the organic layer was concentrated by distillation to give 75 mg of 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. Then, the resulting 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (10 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 5.9 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2Cl)[CH3:4].[IH:15]>O>[OH:1][CH2:2][CH:3]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[I:15])[CH3:4]
Reactant: CC(CO)n1cnc2c(Cl)ncnc21
Reactant: I
Solvent: O
Product: CC(CO)n1cnc2c(I)ncnc21
Reaction time: 0.75 h

Procedure:
9-(1-Hydroxy-2-propyl)-6-chloropurine (I, 1.5 g, 7 mmol) was added to hydroiodic acid (15 ml) at -10° with stirring for 45 min. The precipitate was filtered, neutralized with anhydrous sodium acetate at 5°, and washed with a little cold water (3 times). Recrystallization from ethanol/H2O, gave colorless crystals. Yield=0.9 g (42%) mp=193°-194° uv λmax 276 nm (H2O, pH 5.5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:30][CH:22]3[CH2:21][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)[CH3:13]
Reactant: O=CC1Cc2ccccc2C1
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCC2Cc3ccccc3C2)cc1

Procedure:
A solution of 3-(3-pyridyl)-5-ethyl-1-(4′-aminophenyl)pyrazole (185 mg, 0.7 mmol) and indane 2-carboxaldehyde (0.96 mmol, 140 mg) in methanol (9 mL) and acetic acid (1 mL) was stirred at room temperature for 30 min. Sodium cyanoborohydride (124 mg, 2 mmol) was added and stirring continued at room temperature. After 3 h the solvent was evaporated under vacuum, the residue was taken up in sodium bicarbonate solution (50 mL), and extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. Chromatography of the residue over silica gel (eluant, 35% ethyl acetate in methylene chloride) gave the title compound which was taken up in 50% aqueous acetonitrile containing 1% trifluoroacetic acid and lyophilized to give a light yellow solid. 1H NMR (DMSO-d6) δ 1.2 (3H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz), 2.7-2.76 (3H, m), 3.05-3.12 (4H, m), 6.71 (2H, d, J=8.7 Hz), 6.98 (1H, s), 7.12-7.14 (2H, m), 7.21-7.24 (4H, m), 7.84-7.88 (1H, m), 8.65 (1H, br, d, J=8.2 Hz), 8.71 (1H, d, J=5.1 ),9.2 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[C:6](=[O:12])[NH:7]2.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>C(OCC)(=O)C>[OH:13][CH:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])[NH:7][C:6]1=[O:12]
Reactant: Nc1cccc2c1CC(O)C(=O)N2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c1CC(O)C(=O)N2
Temperature: 0 °C

Procedure:
5-Amino-3-hydroxy-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.68 mmol) is dissolved in ethyl acetate and cooled to 0° C. 4-Trifluoromethylbenzylisocyanate (339 mg, 1.68 mmol) is added slowly with stirring. The reaction mixture is stirred for 1 h at room temperature. The insoluble product is filtered and dried in vacuo. Yield: 103 mg (16%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH:28]=2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]2[CH3:27])[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]3[CH3:27])[CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccnc(Cl)n2)ccc1F
Product: C[C@H]1CNCCN1Cc1cc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)ccc1F

Procedure:
Intermediate 166 from above was coupled with 2-(3,5-difluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 442. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.8 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.7 (d, 1H), 7.5 (t, 1H), 7.0 (d, 2H) 6.7 (d, 1H), 3.8-3.7 (m, 3H) 3.6-3.5 (m, 8H), 3.0 (t, 2H), 1.7 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:24]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391 mg., 0.001 mole) in tetrahydrofuran (15 ml.) is cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution is allowed to warm to ambient temperature and stand for 24 hours. It is then concentrated in vacuo. The residue is suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give 0.229 g. of crude product of melting point 227°-228.5° C. Recrystallization of this material from ethyl acetate gives three crops of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: 0.142 g. of melting point 228°-229.5°, 0.053 g. of melting point 228.5°-229.5° C. and 0.021 g. of melting point 228°-229.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:19]>C(Cl)Cl>[CH2:18]([O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH3:19]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-Amino-4-methylbenzene (1.821 g, 17.0 mmol) was dissolved in DCM (25 mL). N,N-Diisopropylethylamine (3.1 mL, 18.1 mmol) and 4-ethoxy-benzenesulfonyl chloride (2.50 g, 11.3 mmol) were added successively. The reaction mixture was stirred at room temperature overnight and then washed with 10% HCl (2×20 mL) and brine (1×20 mL). Organic phase was dried with sodium sulfate before filtering and removal of solvent. The desired product, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (3.087 g, 94%), was obtained as a colorless solid, in 99.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole(2.96 g, 10.9 mmol) in dry DMF (15 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/479 mg, 12.0 mmol) in dry DMF (15 ml) maintained under nitrogen at room temperature. After stirring for 45 minutes at room temperature benzyl bromide (1.3 ml, 10.9 mmol) was added dropwise. The reaction was stirred for a further 2 hours, diluted with ethyl acetate (75 ml), washed with brine (2×80 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:7) as eluant. (3.68 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[NH:14][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:23][O:24][CH3:25])[C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(C)nc2c(OCc3ccccc3)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
2.0 g (6.3 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole were solved in dimethylformamide (10 ml) and the solution was cooled to 0° C. 151 mg (6.5 mmol) sodium hydride (60%) were added in portions and the reaction was stirred for 20 min. 435 μl (6.3 mmol) 1-Chloro-1-methoxy-methane were added and the reaction was stirred at 0° C. After 2 h the mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=6:1) to afford 0.6 g (26%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][NH:7][C:2]4=[O:1])=[CH:18][CH:17]=3)=[O:14])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: CCOC(=O)c1ccc(N2CCCNC2=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNC4=O)cc3)CC2)c(C)c1
Yield: 77.4 %

Procedure:
Using ethyl 4-(2-oxotetrahydropyrimidin-1-yl)benzoate (84 mg) described in Preparation Example 60 and 1-(3,5-dimethylpyridin-2-yl)piperazine (65 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (103 mg) was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][C:16]#[N:17]>CN(C=O)C.CCOC(C)=O.Cl>[C:16]([CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])#[N:17]
Reactant: N#CCCBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 57% NaH in mineral oil (0.962 g, 22.8 mmol) in dry DMF (100 mL) was added 10 (3.40 g, 24.9 mmol) under nitrogen and the mixture was heated at 80° C. for 1.0 h. A solution of 3-bromopropionitrile (2.81 g, 21.0 mmol) in DMF (5.0 mL) was added at 25° C. and the reaction was heated at 65° C. for 17 h. It was then diluted with EtOAc (250 mL) and 5% aqueous HCl solution (150 mL). The organic layer was separated and then washed with water (4×100 mL). It was dried over MgSO4 (s) and concentrated under reduced pressure. Purification of the residue was carried out by use of column chromatography (EtOAc/hexanes=7.5:2.5) to afford compound 15 (3.510 g, 18.67 mmol) in 75% yield: mp 148-150° C.; Rf(hexanes/EtOAc=1:2) 0.38; UV (EtOH) λmax 260 (ε 13,900); 1H NMR (CD3OD) δ 2.92 (t J=5.8 Hz, 2 H, CH2CN),3.43 (t, J=5.8 Hz, 2 H, CH2N), 8.35 (s, 1 H, HC2), 8.69 (s, 1 H, HC8); MS m/z 188 (M+).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCC1
Yield: 100.5 %

Procedure:
Under nitrogen atmosphere 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.84 g (10 mmol) of cyclopentanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.73 g of the desired product (yield 94%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:8]
Reactant: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOC(=O)[C@@H](N)Cc1ccccc1
Yield: 91 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester (4.4 g, 12.3 mmol) in ethanol (75 mL) was treated with palladium on charcoal catalyst (440 mg, 10% Pd on charcoal) as a slurry in ethyl acetate (10 mL). Hydrogen gas was passed through the suspension for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide L-phenylalanine 2-methoxy-ethyl ester as a colorless oil (2.5 g, 92%). 1H-NMR; d (methanol-d4), 7.35-7.20 (5H, m), 4.27 (2H, m), 3.79 (1H, m), 3.57 (2H, m), 3.38 (3H, s), 3.10 (1H, dd), 2.90 (1H, dd) and 1.64 (2H, s).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12>C([O-])(O)=O.[Na+].C(OCC)C.O>[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and benzo-2,1,3-thiadiazole-4-sulfonyl chloride (2.35 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (2.55 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 5.24 (s, 1H), 2.19 (s, 1H).