Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=4Cl)(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32]>CO>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[CH:27]=4)(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1
Solvent: CO
Product: Cc1nn(C)cc1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1
Reaction time: 24 h

Procedure:
5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (0.082 mmol) was dissolved in methanol (70 mL) and dichloromethane (10 mL) and the reaction vessel flushed with argon before adding 10% palladium on carbon (100 mg). The reaction vessel was charged with hydrogen gas at 50 psi pressure and shaken for 24 hrs. Additional 10% palladium on carbon (50 mg) was added and hydrogenolysis continued at 50 psi pressure of hydrogen gas for an additional 24 hrs. At this time no starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by chromatography using silica eluted with 10% v/v methanol in chloroform to give after concentration in vacuo 1,3-dimethyl-1H-pyrazole-4-sulfonic acid [4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-amide as a colorless solid (38%); EI-HRMS m/e calculated for C19H21N7O4S (M+) 443.1376, found 443.1364.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:14]=2)=[N:5][CH:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=1.[H][H]>[C].[Pd].C(O)C>[CH2:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)(=[O:21])=[O:20])[CH:14]=2)=[N:5][CH:6]=1)[CH3:10]
Reactant: [H][H]
Reactant: C=Cc1cnc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1cnc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)c1
Yield: 94 %

Procedure:
10% palladium-carbon (3.0 mg) as a catalyst was added to an ethanol (2.0 mL) solution of the compound (9.0 mg) obtained in Example 107, and stirred overnight in a hydrogen atmosphere at room temperature. The catalyst was removed through filtration, the solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the entitled compound (8.5 mg, 94%) as a colorless oily substance.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1>CO>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccncn1
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccncn1

Procedure:
7.87 g (53.1 mmol) phthalic acid anhydride and 22 ml (0.24 mol) 4-methylpyrimidine are stirred for 1 h at 140° C. and for 4 h at 21° C. The reaction mixture is then stirred with 15 ml methanol, filtered, and the residue washed with methanol. Further product is obtainable by evaporating the filtrate and stirring the residue with water: m.p.: 168-169° C.); Anal. calc.(C13H8N2O2) C, 69.64%; H, 3.60%; N, 12.49%. found C, 69.8%; H, 3.7%; N, 12.4%; FAB MS (M+H)+=225.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH2:3]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCC1Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (50%, 0.214 g, 4.5 mmol) was added to a solution of 3-benzyl-2-pyrrolidinone (Synthesis, 1996, 8, 941-948; 0.68 g, 3.9 mmol) in THF (15 ml). The solution was stirred at room temperature for 30 minutes. Ethyl bromoacetate (0.48 ml, 4.3 mmol) was added and the mixture stirred for 12 hours. The solvent was removed in vacuo and the residue purified by chromatography eluting with 50% EtOAc in hexane to give the product as a light yellow oil. NMR (90 MHz, CDCl3) 7.2 (m, 5H), 4.2 (m, 3H), 3.25 (m, 1H), 2.75 (m, 2H), 2.3-1.6 (m, 4H), 1.3 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].[CH3:14][Si:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:14][SiH:15]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCO[Si](C)(Cl)OCC
Reactant: CNC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCO[SiH](CN(C)C(=O)c1ccccc1)OCC
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
In a stirring and distillation apparatus according to Example 1, 202.8 g of N-methylbenzamide (1.5 mole) were dissolved in 1500 g of anhydrous toluene at 65° C., and 321.1 g of sodium methanolate solution (25.25% strength, 1.5 mole) were run in, the process was carried out in accordance with Example 6. Then 259.2 g of methyldiethoxychlorosilane (97% pure 1.49 mole) wer slowly added dropwise, and the bottom temperature was maintained at 70° C., and the mixture was then stirred at this temperature for 3 h. The working up was carried out in analogy to Example 1, and 388.5 g (97.5% yield) of a pale, slightly yellowish oily liquid were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:23]=1[NH2:24].C(=O)(O)[O-].[Na+]>COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21][CH3:20])=[N:3][CH:4]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)ncc2Cl)cc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To the compound 2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.005 g, 0.16 mmol) in 1 mL of 2-methoxyethanol was added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g, 0.16 mmol). The mixture was stirred at 110° C. for 18 h. The mixture was basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The aqueous layer was purified by chromatography to give the final product (0.015 g, 20% yield). MS/ES+: m/z=583.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[C:1](=[N:14]/[OH:15])(\[C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)/[CH3:2]
Reactant: CCOc1ccnc(C(C)=O)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccnc(/C(C)=N/O)n1
Yield: 58.6 %

Procedure:
A solution of 2-acetyl-4-ethoxypyrimidine (1.8 g), hydroxylamine hydrochloride (0.83 g) and sodium acetate (2.2 g) in a mixture of ethanol:water (30:10 ml) was heated under reflux for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (×3). the combined extracts were washed with brine, dried and concentrated to give a solid which was washed with hexane to give (E)-2-acetyl-4-ethoxypyrimidine oxime as an off-white solid (1.15 g, 60% yield); 1H NMR (270 MHz): δ1.44(3H,t), 2.38(3H,s), 4.50(2H,q), 6.68(1H,d), 8.48(1H,d), 9.80(1H,brs) ppm.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]1.[C:21]1([N:27]2[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]3[O:40][N:39]=[C:38]4[C:41]5[C:46]([CH2:47][CH2:48][C:37]=34)=[CH:45][C:44]([CH:49]=[O:50])=[CH:43][CH:42]=5)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:50][CH:49]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:38]1=[N:39][O:40][C:36]([C:30]3[CH:29]=[N:28][N:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:31]=3[C:32]([F:35])([F:34])[F:33])=[C:37]1[CH2:48][CH2:47]2)[C:14]1[O:13][CH:17]=[CH:16][C:15]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccoc1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccoc1C(O)c1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
To a stirred solution of diisopropylamine (0.072 mL, 0.508 mmol) in anhydrous THF (0.5 mL) was added a 2.5 M THF solution of n-BuLi (0.203 mL, 0.508 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 15 min. before being cooled to −78° C. A solution of furan-3-carboxylic acid (28.5 mg, 0.254 mmol) in anhydrous THF (1 mL) was added. The reaction mixture was stirred at −78° C. for 30 min. before a solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 89B, 80 mg, 0.195 mmol) in anhydrous THF (1 mL) was added at the same temperature. The mixture was then allowed to warm to room temperature over 30 min. The reaction was quenched with water (3 mL). The mixture was concentrated and the aqueous residue was acidified with 10% aqueous citric acid solution to pH=3. The mixture was extracted with ethyl acetate (2×3 mL). The combined organic solutions were dried (sodium sulfate) and concentrated to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid (110 mg, 0.211 mmol, 108% yield) as green foam solid. Next, 48 mg of the solid was purified by reverse phase preparative HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid, TFA (32 mg) as white solid. The compound had an HPLC retention time=3.42 min. (condition C); LC/MS M+1=522.2; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.88 (1H, d, J=7.9 Hz), 7.54-7.63 (6H, m), 7.48-7.52 (2H, m), 7.47 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=2.0 Hz), 6.56 (1H, s), 3.03 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.9 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.072 g, 0.12 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the product as a white solid (0.007 g, 0.014 mmol, 12%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.45 (d, J=1.6 Hz, 1 H), 7.14 (dd, J=1.6, 8.4 Hz, 1 H), 6.93 (d, J=8.4 Hz, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 6.50 (d, J=2.0 Hz, 1 H), 5.89 (q, J=6.8 Hz, 1 H), 4.86-4.80 (m, 1 H), 4.56-4.85 (m, 1 H), 4.28-4.25 (m, 1 H), 3.99-3.94 (m, 1 H), 3.86-3.82 (m, 1 H), 3.73-3.70 (m, 1 H), 3.56-3.50 (m, 1 H), 3.44-3.31 (m, 2 H), 3.20-3.17 (m, 1 H), 2.86-2.81 (m, 2 H), 2.71-2.66 (m, 1 H), 2.16-2.06 (m, 1 H), 1.96 (d, J=6.8 Hz, 3 H), 1.48-1.25 (m, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2, found 486.4
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 35 °C

Procedure:
9.6 ml (75 mmol) of benzenesulphonic acid chloride are placed in 100 ml pyridine and 7.9 ml (75 mmol) of tert.butylamine are added dropwise at 5° C., whereupon the temperature increases to 35° C. After the addition has ended the mixture is stirred for another hour at 35° C. Then it is poured onto ice water and the crystalline precipitate is suction filtered.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CCO
Reactant: COCCOCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)COCCOC

Procedure:
150 mL solution of 10 g (2-methoxyethoxy)acetic acid and 1 mL conc. sulfuric acid in ethanol was heated for 3 hours under reflux, and then the solvent was removed. The resulting residue was diluted with ethyl acetate and washed with an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed, whereby 9.5 g of the title compound (colorless oil) was obtained.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]CC3C=CC=CC=3)=[O:36])[CH:30]=2)=[O:27])[C:9]1=[O:45])=[O:6])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].CO>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26](=[O:27])[NH:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([OH:37])=[O:36])[C:9]1=[O:45])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)CN(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(c2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
Methanol (20 ml) and 10% palladium carbon (68 mg) were added to 1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea (635 mg), the mixture was stirred at 50° C. under hydrogen atmosphere for 2 hours. The reaction mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was dissolved in 2 N aqueous sodium hydroxide, washed with ether, adjusted to pH 2 with concentrated hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under the pressure, the mixed solvent of isopropyl ether and ethyl acetate was added to the residue for trituration, and collected by filtration, to thereby obtain 144 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCc1cc(Br)ccc1O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1cc(Br)ccc1O[Si](C)(C)C
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
21.3 g (100 mmol) of 2-allyl-4-bromophenol, 12.1 g (120 mmol) of triethylamine (hereinafter referred to as “TEA”), and 120 ml of distilled tetra hydrofuran (hereinafter referred to as “THF”) were loaded into a 300-ml four-necked flask equipped with a reflux pipe with a calcium chloride dry pipe, a dropping funnel, a nitrogen gas introducing pipe, and a mechanical stirring device. The mixture was placed under nitrogen, and was stirred at 0 to 5° C. During the stirring, 11.0 g (120 mmol) of chlorotrimethylsilane were slowly added to the mixture from the dropping funnel. After the completion of the dropping, the resultant was subjected to a reaction at the temperature for 1 hour and then at room temperature for 6 hours. After that, the solvent, excessive trimethylamine, and excessive chlorotrimethylsilane were removed by condensation under reduced pressure, and the residue was washed with water and dried. Thus, 2-allyl-4-bromo-1-trimethylsiloxybenzene was quantitatively obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:49]=[O:50])[O:42]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:49]=[O:50])[OH:42])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1
Yield: 9.1 %

Procedure:
A solution of phenylmethyl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[4-(2-pyridinyl)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate in AcOH/water (5 mL, 4:1) was stirred at rt for 48 h. The solvents were removed under vacuum and the residue was purified by RP-HPLC to provide the title compound (32 mg, 9.1%) as light-yellow gum.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Si]([O:14][CH2:15][C@@H:16]([N:25]1[CH:29]=[C:28]([C:30]([O:32]C)=O)[N:27]=[CH:26]1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C(C)(C)C)(C)C>CO>[OH:14][CH2:15][C@@H:16]([N:25]1[CH:29]=[C:28]([C:30]([NH:5][OH:6])=[O:32])[N:27]=[CH:26]1)[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cn([C@@H](CCc2ccccc2)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1cn([C@H](CO)CCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A powder of NaOMe (417 mg, 7.72 mmol) was added to an ice cooled solution of hydroxylamine hydrochloride (536 mg, 7.72 mmol) in methanol (5 ml). After 30 minutes, methyl (S)-1-[1-(tert-butyldimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6)(389 mg, 1.0 mmol) in methanol (2 ml) was added to the mixture and the resulting mixture was stirred at reflux for 3 day. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 1N HClaq. The resulting mixture was washed with CHCl3. The aqueous layer was purified by HP-20 (40 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-1-[1-hydroxy-4-phenyl-2-butyl]-imidazole-4-carbohydroxamic acid (92.5 mg, 43.5%) as an amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][N:11]4[N:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[N:18][N:19]=2)=[CH:27][C:26]=1[C:33]([F:34])([F:36])[F:35]
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nnc(-c3ccn4ncnc4c3)o2)cc1C(F)(F)F
Yield: 62 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 62%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[O:29][CH:30]=2)[N:3]=1.Cl.[CH3:39][NH:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:24][C:4]3[N:3]=[C:2]([N:40]([CH3:39])[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=4)[C:5]=3[C:22]#[N:23])[N:27]=2)=[CH:32][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
108 mg (0.20 mmol) of the compound from Example 103A are dissolved in 3 ml of dry DMF, and 54 mg (0.39 mmol) of methyl N-methylglycinate hydrochloride and 59 mg (0.59 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. The solvent is then removed on a rotary evaporator and the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.