Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:26](O)(=[O:28])C>>[CH:26]([C:3]1[CH:4]=[C:5]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:2]=1[OH:1])=[O:28]
Reactant: CC(=O)O
Reactant: O=S(=O)(O)c1ccc(O)c2ncccc12
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(S(=O)(=O)O)c2cccnc2c1O
Yield: 45 %

Procedure:
8-Hydroxyquinoline-5-sulfonic acid monohydriate (0.015 mol, 3.65 g), hexamethylenetetramine (0.225 mol, 21.0 g) and acetic acid (750 mL) were stirred and heated at 97°-100° C. for 6 hrs. After cooling, acetic acid was removed under reduced pressure, and the residue was treated with acetone (1 L) to give a precipitate which was filtered off and washed with additional acetone. Water (30 mL) and concentrated hydrochloric acid (15 mL) were then added to the solid. The resulting solution was refluxed for 2 hours. Then, the mixture was concentrated under reduced pressure and left for crystallization. The solid was filtered off, washed with water and dried to give pure 7-formyl-8-hydroxyquinoline-5-sulfonic acid in 45% yield.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].S(Cl)(Cl)=O.[CH2:20](O)[CH3:21]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:20][CH3:21])=[O:11])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Solvent: O=S(Cl)Cl
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 85 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, 30 ml of ethanol, and 3.36 grams of thionyl chloride were added into 100 ml three-necked flask, and refluxed until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.9 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 85%.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C:21]([O:23]CC1C=CC=CC=1)=O)[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:20][C:21]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:39])=[O:23])[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1ccccc1
Reactant: CNCc1ccccc1
Agent: [Pd]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
A solution of 1.03 g (2.52 mmole) of 3-[2(R)-benzyl-3-(benzyloxycarbonyl)propionyl]-4(S)-isopropyl-2-oxazolidinone (prepared as described in Preparation 13) in 20 ml of ethanol was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 100 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The residue was dissolved in 50 ml of anhydrous tetrahydrofuran, and 0.39 ml (3.02 mmole) of N-benzyl-N-methylamine, 0.46 ml of 95% diethyl cyanophosphonate and 0.42 ml of triethylamine were added, in that order, to the solution, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure column chromatography through silica gel using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 1.04 g (yield 98%) of the title compound as white crystals, melting at 60°-62° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[N:3]=[CH:2]2
Reactant: COc1cccc2c(Cl)nc(C)nc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc2cnc(C)nc12
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of 4-chloro-8-methoxy-2-methylquinazoline (5.12 g), 10% palladium on carbon (512 mg) and triethylamine (3.72 g) in ethyl acetate (51 ml) was stirred under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in methylene chloride, and the solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methylene chloride-methanol) to give 8-methoxy-2-methylquinazoline (3.07 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=[O:5].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:6][C:4](=[O:5])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(OC)C(C)=O
Product: COC(OC)C(=O)C=CN(C)C
Reaction time: 16 h

Procedure:
1,1-dimethoxyacetone (pyruvic aldehyde dimethyl acetal, Aldrich Chemical Co.) (3 cm3) was added dropwise with stirring to tert-butoxy-bis(dimethylamino)methane (Fluka Chemie AG) (5 cm3) and stirring continued at ambient temperature for 16 hours. The low-boiling impurities were removed by evaporation under reduced pressure. This left an orange oil (5.82 g) (1H NMR (CDCl3): δ2.88(3H,br s); 3.10(3H,br s); 3.40(6H,s); 4.58(1H,s); 5.34(1H,d); 7.76(1H,d)).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@H]3C[C@@H]3CN)cccc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 1-[(1S,2S)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (300 mg, 1.09 mmol) and triethylamine (305 μL, 2.19 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (124 μL, 1.31 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (242 mg, yield 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A solution of 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (8.1 g, 22.8 mmol), (S)-(+)-2-methylpyrrolidine (2.33 g, 27.36 mmol), K2CO3 (6.93 g, 50.16 mmol) in acetonitrile (76 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-methylpyrrolidine (834 mg, 9.79 mmol), and the temperature of the reaction mixture was maintained at 80° C. for 20 h. The heating was removed and the solution was concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.43 g (40% yield) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([O:12][CH3:13])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(F)ccc2ccc(O)nc12
Product: COc1c(F)ccc2ccc(Cl)nc12
Yield: 90.5 %

Procedure:
A mixture of 7-fluoro-8-methoxy-2-quinolinol (4a) (2.26 g, 11.7 mmol) and POCl3 (5.5 mL, 60 mmol) was refluxed for 1.5 hours. The contents were concentrated and neutralized with NaHCO3 and the mixture heated with water and AcOEt. The solution was filtered to remove undissolved impurities, followed by extraction. The organic layer was washed with saturated NaCl and dried with MgSO4. The product was recrystalized from ***CHCl3-hexanes, which yielded white crystals (2.24 g, 90% yield): mp 85-86° C.; 1H NMR (400 MHz, CDCl3) 8.06 (d, J=8.8Hz, 1H) 7.48 (dd, J=8.8, 5.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.35 (dd, J=9.2, 2.4 Hz, 1H), 4.23 (d, J=2.4 Hz, 3H). 19F NMR (376 MHz, CHCl3) −127.35 (dd, J=10.9, 2.6 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:39])[N:10]([C@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][C:41]1([CH3:65])[CH2:50][CH2:49][C:48]2[N:47]=[CH:46][N:45]=[C:44]([N:51]3[CH2:57][C:56]4[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][C:55]=4[O:54][CH2:53][CH2:52]3)[C:43]=2[CH2:42]1>>[C:1]1([CH2:7][O:8][C:9](=[O:39])[NH:10][C@H:19]([C:21]2[NH:22][C:23]3[C:24]([N:30]=2)=[N:25][CH:26]=[C:27]([C:59]2[CH:60]=[CH:61][C:55]4[O:54][CH2:53][CH2:52][N:51]([C:44]5[C:43]6[CH2:42][C:41]([CH3:40])([CH3:65])[CH2:50][CH2:49][C:48]=6[N:47]=[CH:46][N:45]=5)[CH2:57][C:56]=4[CH:58]=2)[CH:28]=3)[CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1S)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (br, 1H), 8.36 (br, 1H), 8.09 (br, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.42 to 7.25 (m, 5H), 7.10 (d, 1H), 5.17 to 5.03 (dd, 2H), 4.73 (s, 2H), 4.61 (m, 1H), 4.37 (m, 1H), 3.95 (m, 1H), 2.79 (t, 2H), 2.48 (s, 2H), 1.72 to 1.56 (m, 5H), 0.90 (s, 6H); MS (EI) for C35H37N7O3: 604 (MH+).
Reaction SMILES: C[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:12]([CH3:14])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][C:7]=1[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1=C(/C=C/C(C)N)C(C)(C)CC1

Procedure:
A solution of β-ionone (10.0 g., 52 mmol), ammonium acetate (40.0 g., 520 mmol) and sodium cyanoborohydride (3.27 g., 52 mmol) in methanol (150 ml) is stirred at room temperature for 3 days. The mixture is then made acidic to a pH less than 2 with concentrated hydrochloric acid, and most of the solvent is evaporated under vacuum. Water (150 ml) is added and the solution is washed with two 50 ml portions of ether. The aqueous solution is then made basic to pH greater than 10 with solid sodium hydroxide. The mixture is extracted with two 50 ml portions of ether, and the combined extracts washed with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated to yield a colorless oil (2.3 g.). The product is isolated by HPLC on a bonded C18 reverse phase column using methanol as the eluent to yield approximately 1 g. of a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cccs1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1cccs1)C(=O)N2
Yield: 19 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2-thiophene carboxaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH2:39]([OH:41])[CH3:40].C(N(CC)CC)C>ClCCl>[CH2:39]([O:41][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22])[CH3:40]
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 56 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride (0.1 g) in dry dichloromethane (5 mL) was treated with absolute ethanol (0.2 g) and triethylamine (0.1 g) for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (1:4 to 2:3 by volume) to afford the title compound as a white solid (0.057 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.77 (dd, 1H), 7.48-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.61 (d, 1H), 6.40 (d, 1H), 4.37 (d, 1H), 4.17 (qd, 2H), 3.80 (t, 5H), 3.66 (t, 4H), 3.29 (d, 1H), 2.95-2.86 (m, 1H), 2.57 (d, 1H), 2.44-2.34 (m, 3H), 1.25 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (5 g), pyridine (3.36 ml) and dichloromethane (50 ml) was added benzyloxycarbonyl chloride (3.1 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate (30 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with diisopropyl ether to give ethyl 2-{[(benzyloxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (5.1 g)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3OC)nc2n(CCC)c1=O
Yield: 50.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.25 g (5.52 mmol) of 5,6-diamino-1,3-dipropyluracil and 1.35 g (6.08 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.14 g (yield 50%) of Compound 15 as white needles.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.Cl>CO>[N:30]1([CH:27]2[CH2:26][CH2:25][CH:24]([O:23][C:14]3[C:13]4[C:12]5[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:29][CH2:28]2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: Cl
Solvent: CO
Product: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (850 mg, 1.64 mmol, 1.00 equiv) in methanol (20 mL) was added hydrochloric acid (2 M, 1.0 mL) and the resulting mixture was stirred for 1 hr at 0° C. in a water/ice bath. After completion, the reaction was quenched with sodium bicarbonate (sat.) and extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with chloroform/methanol (15:1) to afford 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (600 mg, 91%) as a colorless oil. MS (ES): m/z 404 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[Cl:17][C:18]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])=[CH:26][C:18]=1[Cl:17]
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[C:34](=[CH:45][CH:46]=1)[C:35](OCC1C=CC=CC=1)=[O:36]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:48](=[O:49])[NH:47]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(C(=O)OCc2ccccc2)c(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C(=O)O)c(N)c3)c(=O)[nH]c2c1
Yield: 3.1 %

Procedure:
500 mg (1.23 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg (1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 15 mg (yield 3.1%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.82 (3H, s), 6.58 (1H, s), 6.80 (1H, d), 7.16 (1H, d), 7.56 (1H, s), 7.80 (1H, d), 7.90 (1H, d), 11.49 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1>>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3,5-dimethylisoxazol-4-ylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 325.0 (M+H)+, retention time 1.61 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>O1CCOCC1>[CH:28]1([NH:31][C:2]2[N:7]=[CH:6][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:11][C:10]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[O:20])=[N:9]3)=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(Cl)nc3)n2)CC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(NC4CC4)nc3)n2)CC1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (200 mg) obtained in Example 110 in dioxane (1.0 mL), cyclopropylamine (1.0 mL) was added. The mixture was stirred at 100° C. for 3 days in a sealed tube, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated aqueous sodium hydrogencarbonate, and then dried over magnesium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1 mL). The solution was purified through preparative high-performance liquid chromatography (eluent: water-acetonitrile), to thereby give the title compound as an oily product (19.6 mg, 9%).