Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2]>CO.O=[Pt]=O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH2:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2c3ccccc3ncn2c1
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)c1cc2n(c1)CNc1ccccc1-2
Reaction time: 3 h

Procedure:
The product of Example II (2.5 g, 0.01 m) was dissolved in MeOH (250 ml). The catalyst, PtO2 (0.5 g), was added and the mixture was hydrogenated at 42 p.s.i. for 3 hrs. Filtration and removal of the solvent in vacuo yielded a white solid. Crystallization from MeOH afforded the product as a white solid; m.p. 140°-141° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:28]=1[CH2:29][O:30]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[C:28]([CH2:29][OH:30])=[C:34]([C:2]3[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:35]=[CH:36][CH:37]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)nc1C(N)=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)nc1C(N)=O
Yield: 12 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (intermediate-1) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (12% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=2.7 Hz, 1H), 7.87-7.71 (m, 5H), 7.50-7.44 (m, 2H), 7.30 (dd, J=1.2, 7.8 Hz, 1H), 4.38-4.33 (m, 2H), 4.00 (s, 3H), 1.39 (s, 9H). LC-MS calcd for C24H24FN5O3 (m/e) 449.19, obsd 450 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1.C(N(CC)CC)C>C(OCC)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:1](=[O:3])[CH3:2])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(Br)cc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
Acetyl chloride (2.0 g) in diethyl ether (10 ml) was added dropwise to a stirred, cooled solution of 5-bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5.0 g), prepared as in Example 5(e), and triethylamine (2.5 g) in diethyl ether (40 ml). After stirring for 3 hours at room temperature the mixture was washed with water three times, dried over magnesium sulphate and run down to yield 5 g of crude product, mp 73°-80° C., which was recrystallised from petroleum ether (80°-100° C.) with charcoaling to give 4 g of pure product, mp 83°-85° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=1)=[O:12].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:20][O:21][C:32](=[O:33])[O:22]2)[CH:14]=1)=[O:12])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24]
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C1OCC(c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
A 300 mg portion of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and 200 mg of 1,1′-carbonyldiimidazole were dissolved in 7 ml of Tol and stirred at 80° C. for 12 hours. After concentration of the reaction liquid, the thus formed residue was purified by a silica gel column chromatography to obtain 30 mg (9%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(2-oxo-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione as a yellow solid from a chloroform-methanol (10:1) eluate. ES+: 445
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([NH2:21])=[N:5][C:6]([C:8]1[CH:19]=[CH:18][C:17]2[C:16]3[CH:15]=[CH:14][S:13][C:12]=3[C:11](=[O:20])[C:10]=2[CH:9]=1)=[O:7]>CO>[NH2:21][C:4]([NH2:3])=[N:5][C:6]([C:8]1[CH:19]=[CH:18][C:17]2[C:16]3[CH:15]=[CH:14][S:13][C:12]=3[CH:11]([OH:20])[C:10]=2[CH:9]=1)=[O:7]
Reactant: NC(N)=NC(=O)c1ccc2c(c1)C(=O)c1sccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(N)=NC(=O)c1ccc2c(c1)C(O)c1sccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A 156 mg portion of sodium borohydride was added to a 10 ml methanol suspension of 280 mg N-(diaminomethylene)-8-oxo-8H-indeno[2,1-b]thiophene-6-carboxamide, followed by stirring at room temperature for 30 minutes. After evaporation of the solvent, the solid precipitated by adding water was purified by Chromatorex (DMF/chloroform) to obtain 284 mg of N-(diaminomethylene)-8-hydroxy-8H-indeno[2,1-b]thiophene-6-carboxamide as a pale green solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@H:39]([NH:41][CH:42]([CH3:44])[CH3:43])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@H:39]([N:41]([CH:42]([CH3:44])[CH3:43])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)N[C@H](C)COCc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and ((R)-2-benzyloxy-1-methyl-ethyl)-isopropyl-amine as described for example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1>[CH3:11][O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(CO)on1
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COCc1cc(C(C)=O)no1
Temperature: 60 °C

Procedure:
To a solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (1.00 g, 7.09 mmol) in dry THF (20 mL) under an atmosphere of nitrogen was introduced cesium carbonate (2.31 g, 7.09 mmol) and methyl iodide (5.03 g, 35.43 mmol). The reaction mixture was warmed to 60° C. for 16 hr, cooled to RT and the solids removed by filtration. The filtrate was re-treated with additional cesium carbonate (4.31 g, 13.23 mmol) and methyl iodide (9.59 g, 67.58 mmol) and warmed to 60° C. for 34 hr. After cooling to RT, the reaction mixture was filtered, concentrated in vacuo and the residue re-dissolved in EtOAc (50 mL). The EtOAc solution was washed with water (25 mL), brine (25 mL), dried (Na2SO4) and filtered. After concentrating the filtrate in vacuo, the residual oil was purified by silica gel flash column chromatography (95:5-50:50 gradient of heptane/EtOAc) to furnish the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 2.66 (3H, s), 3.44 (3H, s), 4.59 (2H, s), 6.64 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]([O:27]C)=[O:26].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Yield: 92.8 %

Procedure:
A mixture of methyl {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetate (217 mg, 0.477 mmol), prepared in the previous step, and 1 N NaOH (716 μL, 0.716 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2.25 h. The reaction was filtered, acidified by the addition of 3 mL of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (195 mg, 92%) as a white solid, mp 222-230° C. Elemental Analysis for C21H14BrNO3S+0.15H2O Calc'd: C, 56.94; H, 3.25; N, 3.16. Found: C, 57.19; H, 3.18; N, 3.04.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[C@@H:10](Br)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:15]([C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCc1ccccc1)[C@@H](Br)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 52.5 °C
Yield: 99.62 %

Procedure:
To a reaction flask was charged (2S)-N-benzyl-2-bromo-3-hydroxypropanamide (80.0 g) and sodium azide (30.23 g) in N,N-dimethylformamide (480 ml) and raised the temperature to 50-55° C. and maintained for 4-5 hours. Stopped heating and cooled the reaction mixture to 20-25° C. and charged DM water (400 ml), adjusted pH of the reaction mixture to 9-9.5 using 5% NaHCO3 solution. Extracted the reaction mass with ethyl acetate (1×800 ml, 2×280 ml). Separated the organic layer and combined all ethyl acetate layers, washed with saturated ammonium chloride solution (2×240 ml). Concentrated the solvent ethyl acetate under reduced pressure to get oily compound of (2R)-2-azido-N-benzyl-3 -hydroxypropanamide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[CH3:15][O:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:15][O:16][CH3:17])[C:6]#[N:7]
Reactant: COCCl
Reactant: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C#N)c([N+](=O)[O-])c1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-hydroxy-3-methoxy-2-nitrobenzonitrile 1.00 g, chloromethyl methyl ether 0.47 mL (6.18 mmol) and potassium carbonate 3.56 g (25.8 mmol) in N,N-dimethylformamide 10 mL was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted into diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. Silica gel chromatography (n-hexane/AcOEt=4/1) afforded the title compound 1.03 g as colorless solid. Yield 83.5%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[C:34]([CH:31]5[CH2:33][CH2:32]5)=[O:35])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A mixture of the compound (0.1 g) obtained in Example 4, cyclopropylcarbonyl chloride (25 mg), triethylamine (76 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (67 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][N:11](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)CN1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1NC[C@H]1NC(=O)OC(C)(C)C
Yield: 70.9 %

Procedure:
10% Pd/C (100 mg) was added to a solution of trans(±)-3-(tert-butoxycarbonyl)amino-1-(diphenylmethyl)-2-ethylazetidine obtained in Example (234d) (530 mg, 1.45 mmol) in methanol (7 mL), and the mixture was stirred in a hydrogen stream at 40° C. for 13 hours. The reaction solution was filtered, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution was added to the resulting residue. The aqueous layer was washed with ethyl acetate, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate and a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the filtrate was concentrated under reduced pressure to obtain 206 mg of the title compound as a white solid (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.[OH-].[Na+].CO.Cl>O.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A stirred mixture of methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (245 g, 0.45 mol), NaOH (36 g, 0.90 mol) dissolved in water (225 mL), methanol (0.5 L) and THF (1.2 L) was heated at 65° C. for 90 min. The mixture was cooled to room temperature, treated with 6 N HCl (150 mL) and stirred at room temperature for 30 min. The resulting precipitate was collected by filtering, washed with water (2×1 L) and dried overnight at 45° C. in a vacuum oven to yield 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (162 g, 68%). A second crop of material was similarly obtained (27.2 g, 11%). 1H NMR (400 MHz, DMSO-d6): 8.48 (d, J=9 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 8.17 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 7.72 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.46 (m, 1H), 1.32 (d, J=7 Hz, 6H). ES-LCMS m/z 533 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:9]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccnc(Cl)c1)c1cc(Cl)ccc1O
Yield: 12.2 %

Procedure:
Using 5-chlorosalicylic acid and 4-amino-2-chloropyridine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:15])[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C[Si](C)(C)[O-].[K+].O>C1COCC1>[Br:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[C:5]([CH3:15])([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2
Reactant: COC(=O)C1(C)CCc2cc(Br)ccc21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CCc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
A solution of (rac)-5-bromo-1-methyl-indan-1-carboxylic acid methyl ester (1.318 g, 4.9 mmol) and potassium trimethylsilanolate (3.14 g, 24.5 mmol) in dry THF (25 ml) was stirred at reflux for 1 h. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted two times with tert-butyl methylether. The pH of the aqueous layer was carefully adjusted to 3 by addition of 1N HCl and the aqueous layer was extracted two times with EtOAc. The combined EtOAc-layers were washed with brine, dried with Na2SO4 and evaporated. Toluene was added to the remaining residue and it was evaporated to remove water. The title compound was obtained as light yellow solid (1.204 g, 96%). MS: 252.7 [M−H]−.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[O:7][C@@H:6]1[C@H:22]([OH:53])[CH:23]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[NH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:47])[C@H:30]([C@@H:42]([OH:46])[CH:43]([CH3:45])[CH3:44])[NH:31]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>[Pd].CO>[NH2:31][C@@H:30]([C@@H:42]([OH:46])[CH:43]([CH3:45])[CH3:44])[C:29]([NH:28][CH2:27][CH2:26][CH2:25][NH:24][CH:23]([C@H:22]([C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[O:7]1)[OH:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:47]
Reactant: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](O)C(C)C)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](N)[C@@H](O)C(C)C)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Ethyl (5S)-12-[(R)-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (obtained from Example 36) was hydrogenated using 10% palladium on carbon in absolute methanol under atmospheric pressure, to give ethyl (3R)-2-[(3-{[(2S,3S)-2-amino-3-hydroxy-4-methylpentanoyl]amino}propyl)amino]-3-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate as a white amorphous solid [MS (ES) 616.1 (M+H)].
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])OC(C)(C)C)=[O:29])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O>[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:29])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 65.1 %

Procedure:
TFA (1 ml) was added to tert-butyl ((1R,2S)-2-{[(4aR*,5R*,10bR*)-5-phenyl-3,4,4a, 5,6,10b-hexahydrobenzo[h]-1,6-naphthyridin-1(2H)-yl]carbonyl}cyclohexyl)carbamate (69 mg, 0.14 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, and the mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dimethylacetamide (2 ml), benzoyl chloride (28 mg, 0.17 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and eluted with hexane-ethyl acetate (7:1-3:1, v/v) to give the title compound (45 mg, 65%) as a colorless amorphous form.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].S(Cl)(Cl)=O.C[N:40](C=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH2:40])=[O:29])=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid, RD141 (Formula 51) (60 mg, 0.12 mmol) in DMF (3 mL) was added thionyl chloride (0.01 mL, 0.15 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then ammonia was bubbled into the mixture. The mixture was partitioned with ethyl acetate (25 mL) and water (25 mL). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (37 mg, 61%) as a white powder. 1H NMR δ 7.97 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.85 (dd, 1H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.22 (d, 2H, J=8.3 Hz), 5.59 (br s, 2H), 2.77 (t, 21-1, J=7.5 Hz), 2.62-2.68 (m, 2H), 2.51-2.59 (m, 2H), 2.31 (t, 2H, J=7.5 Hz), 2.16-2.25 (m, 1H), 2.05 (p, 2H, J=7.5 Hz), 1.57-1.70 (m, 1H).