Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.C(O)(=O)C.C(O)(=O)C.[CH3:25][N:26]([CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1)[CH3:27]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][N:26]([CH3:27])[CH3:25])[CH2:30][CH2:31]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.54 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (190 mg, 0.68 mmol) to afford the desired product (150 mg, 68%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 5.05-4.95 (m, 1H), 3.09 (s, 3H), 2.34-2.24 (m, 8H), 2.18 (d, J=7.0 Hz, 2H), 2.00-1.92 (m, 2H), 1.57-1.50 (m, 1H), 1.42-1.30 (m, 2H), 1.24-1.12 (m, 2H); ESI MS m/z 397 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH3:2].[NH2:21][C:22]1[C:27]([CH:28]=O)=[CH:26][CH:25]=[CH:24][N:23]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:28][C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CN(CCCC(C)=O)C(=O)OC(C)(C)C
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C

Procedure:
A solution of 2-6 (28 g, 97.4 mmol), 2-amino-3 formylpyridine (15.5 g, 127 mmol), proline (11.2 g, 97.4 mmol) in ethanol (250 mL) was heated at reflux for 15 h. After cooling and evaporation, the residue was chromatographed (silica gel, 1:1 chloroform/ethyl acetate) to give 2-7 as a yellow oil. TLC Rf =0.41 (silica, 70:25:5 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 9.09 (m, 1H), 8.14 (m, 2H), 7.43 (m, 2H), 4.17 (q, 2H, 7 Hz), 3.9 (2s, 2H), 3.43 (q, 2H, J=7 Hz), 3.07 (m, 2H), 2.18 (m, 2H), 1.42 (s, 9H), 1.25 (m, 3H).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.CCO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[C:15]1(=[O:16])[C:11]2([CH2:10][CH2:9][NH:8][CH2:19][CH2:18]2)[CH2:12][C:13](=[O:17])[NH:14]1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CC2(CCNCC2)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 8-benzyl-2,8-diaza-spiro[4.5]decane-1,3-dione (28.3 g, 0.11 mol) and Pd(OH)2 (8.5 g) in 2 l of flask, EtOH (438 ml) and acetic acid (5.5 ml) are added at ambient temperature. The reaction mixture is stirred under H2 at room temperature for 15 h. The catalysts are removed by filtration and EtOH is evaporated down to give 2,8-diaza-spiro[4.5]decane-1,3-dione in quantitative yield. To a suspension of 2,8-diaza-spiro[4.5]decane-1,3-dione (4.2 g, 25.2 mmol) in dichloromethane (60 ml), 1N NaOH (26 ml, 26 mmol) and di-t-butyldicarbonate (6.1 g, 27.7 mmol) in dichloromethane (20 ml) are added at ambient temperature. The reaction mixture is stirred for 15 h. 10% Citric acid is added to the reaction mixture and the pH of the mixture is adjusted to 5. The combined extracts are washed with brine, dried over magnesium sulfate and concentrated under vacuum to give solid product, which filtrated with diethyl ether.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH3:21][S:22]([OH:25])(=[O:24])=[O:23]>C(O)(C)C>[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[CH3:19][N:18]1[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:15][N:16]=[N:17]1
Reactant: Cn1nnnc1N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: Cn1nnnc1N1CCC(N)CC1
Temperature: 44 °C
Yield: 91.1 %

Procedure:
A mixture of tert-butyl[1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-yl]-carbamate (39.0 g, 0.138 mol) and methanesulphonic acid (23 mL, 0.354 mol) in isopropanol (290 mL) was stirred at 44° C. over night. The reaction mixture was cooled slowly to 0° C. and stirred for 2 hours. The precipitate was washed with cold isopropanol (2×25 mL) and dried to give 1-(1-methyl-1H-tetrazol-5-yl)-piperidin-4-amine methanesulphonic acid salt as a white powder (35.0 g). 1H NMR (300 MHz, MeOH-d4) ppm 1.75-1.94 (qd, J=12, 3 Hz, 2H) 2.03-2.19 (d, J=12 Hz, 2H) 2.71 (s, 3H), 3.08-3.26 (t, J=13 Hz, 2H) 3.37-3.50 (m, 1H) 3.63-3.87 (d, J=13 Hz, 2H) 3.94 (s, 3H) 4.74-4.90 (d, J=1 Hz, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][OH:28])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][C:1]4=[O:2])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene in toluene (1.9 ml of a 20% commercial solution, 3.5 mmol) is added within five minutes to a solution of 2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-ethanol (0.88 g, 2.6 mmol) and triethylamine (1.7 ml, 11.7 mmol) in absolute THF (20 ml) at 50° C. After stirring the resulting suspension for one hour at room temperature it is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 162–163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([OH:34])=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([O:34][CH3:37])=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(O)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (24.5 mg, 0.048 mmol) in DMF (2 mL) were added Cs2CO3 (31.5 mg, 0.097 mmol) and MeI (6 μL, 0.097 mmol). The reaction was stirred at room temperature for 15 minutes and then diluted with EtOAc (40 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column with 0 to 100% EtOAc/hexanes to afford 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C28H33ClN6O2 [M+H]+=521. found=521.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44]C(C)C)=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)C[CH2:7]1)=[O:5].O.[OH-].[Na+].O1CCO[CH2:58][CH2:57]1>C(OCC)(=O)C>[CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:58][CH2:57][CH2:7]1)=[O:5]
Reactant: C1COCCO1
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CCC2
Temperature: 120 °C

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (110 mg, 0.156 mmol) was dissolved in 1,4-dioxane (6 mL) and transferred to a 20 ml microwave vessel. Water (2 mL) and a solution of 6M NaOH (2 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluorobenzamide (53 mg, 0.096 mmol) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.94 (m, 2 H), 2.12 (br. s., 6 H), 2.68 (br. s., 2 H), 3.24 (s, 2 H), 3.70 (t, J=5.95 Hz, 2 H), 3.84 (s, 3 H), 6.29 (d, J=1.10 Hz, 1 H), 6.83 (br. s., 1 H), 6.98 (br. s., 1 H), 7.38-7.51 (m, 2 H), 8.12 (br. s., 3 H), 8.42 (br. s., 1 H), 9.83 (br. s., 1 H), 11.37 (d, J=1.01 Hz, 1 H). (ESIMS (M+H)+=551)
Reaction SMILES: [CH3:1][C@@H:2]1[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[C:4](=[O:15])[CH2:3]1.C(N(CC)CC)C.O>CCN(CC)CC.C(O)=O.C(O)=O.C(#N)C>[OH:15][CH:4]1[CH2:3][C@H:2]([CH3:1])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]1=2
Reactant: C[C@H]1CC(=O)c2cc(S(N)(=O)=O)sc2S1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: C[C@H]1CC(O)c2cc(S(N)(=O)=O)sc2S1
Temperature: 28 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
A solution of catalyst RuCl(p-cymene)[(S,S)-Fs-DPEN] (27.4 mg, 0.0385 mmol) in TEAF (1.5 g, molar ratio 5:2) was added to a mixture of (6S)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (1.0 g, 3.80 mmol) in formic acid:triethylamine (2.16 g, molar ratio 5:2) under nitrogen at 28° C. After 16 hours, a solution composed of RuCl(p-cymene)[(S,S)-Fs-DPEN] (27.5 mg, 0.0386 mmol) in acetonitrile (1.2 g) was added to the mixture. After five days of stirring at 28° C., demineralised water (10.7 g) was added to the reagent mixture and the temperature was lowered to 10° C. The solid was filtered to obtain (6S)-4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide as a mixture of trans:cis diastereoisomers equal to 61.7:38.3 (0.32 g, yield 32%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C1(C)C=CC=CC=1.[BH4-].[Na+]>ClCCl.O.CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccc(Br)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask fitted with a Dean-Stark trap was introduced 2-bromo-5-methoxybenzaldehyde (5.68 g, 26.41 mmol), cyclopropylamine (3.02 g, 52.83 mmol) and toluene (70 ml). The reaction mixture was stirred at room temperature for 1 hour and then at reflux for 4 hours. The solution was then concentrated to give a yellow oil to which was added methanol (30 ml). The reaction mixture was cooled on icebath followed by portionwise addition of sodium borohydride (2.00 g, 52.83 mmol). After complete addition, the reaction mixture was stirred 2 hours at room temperature, and then water (70 ml) was added. The crude product was isolated by extraction with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, and finally evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C([O:56][C:57]([CH2:59]CCCCOS(C1C=CC(C)=CC=1)(=O)=O)=[O:58])(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:59][C:57]([OH:58])=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Solvent: CCOCOCC
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of diethoxymethane is cooled to 0° C. At 0° C., 78 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid-tert-butyl ester, dissolved in 40 ml of tetrahydrofaran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for 3 hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of methanol. 50 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for one hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@@:41]([CH3:47])([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:47][C@:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:45][CH3:46])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)N[C@H](CC(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 102.1 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (S)-2-(tert-butoxycarbonylamino)-2-methylbutanoic acid (320 mg) were used, whereby tert-butyl (2S)-2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxobutan-2-ylcarbamate (881 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (241 mg) was yielded.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(tert-Butoxycarbonyl)-piperidine-3-carboxylic acid (3.00 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (7.3 mL; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 15 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH+ 479.4
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][N:12]2[N:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=[N:16]2)[N:3]=1
Reactant: Cc1nc(Br)cs1
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1nc(C#CCCn2nc3ccccc3n2)cs1
Yield: 50.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-bromo-2-methylthiazole (30 mg, 0.13 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (30 mg, 0.17 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 18 mg (66 μmol, 50%) of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH2:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccccc1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccccc1-n1ccc2ccccc21
Yield: 71.1 %

Procedure:
Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled with 2-bromoaniline (0.206 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 5:1) provided 0.148 g (71% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.64 (m, 1H), 7.18 (m, 6H), 6.82 (m, 2H), 6.64 (m, 1H), 3.52 (bs, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.CO>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 85 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 85% of theory, C28H30N6O3 (498.6) Rf value: 0.30 (silica gel; dichloromethane/methanol=5:1) ##EQU38##
Reaction SMILES: C(S[C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:22][C:19]([CH3:20])([CH3:21])[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:25][C:26]2[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=2[F:32])=[O:24])=[CH:17][CH:16]=1)=[O:23]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-fluorophenol.