Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1
Reactant: C[C@@H]1C[C@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl ((1S,2R,3R,5S)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate in 98% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.71 min.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[O:9])=[CH:14][CH:13]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccncc1)c1ccc(F)cc1
Reaction time: 6 h
Yield: 75.5 %

Procedure:
To a stirred and cooled (ice-bath) solution of 141.5 parts of 4-pyridinecarbonyl chloride hydrochloride in 400 parts of fluorobenzene were added portionwise 399 parts of aluminum chloride. Upon completion, the whole was slowly heated to reflux and stirring at reflux was continued for 6 hours. The reaction mixture is cooled, poured onto crushed ice and acidified with 240 parts of a hydrochloric acid solution 10N. The layers were separated. The acid aqueous phase was washed twice with 180 parts of methylbenzene and strongly alkalized with a sodium hydroxide solution 60%. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was dissolved in 900 parts of methylbenzene and the solution was treated with activated charcoal. The latter was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 152 parts (75.5%) of (4-fluorophenyl)(4-pyridinyl)methanone; mp. 85.5° C. (intermediate 25).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (4.6 g, 26 mmoles), rhodanine (3.5 g, 25 mmoles), sodium acetate (7.5 g, 91 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is stirred into ice-water (250 ml) and the precipitate is filtered off, rinsed three times with water and dried. Recrystallization from methanol gave the pure product (2.9 g), mp 203°-204° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1)(=O)=O.[CH3:16]O>>[CH3:16][O:5][CH2:6][CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1
Reactant: CS(=O)(=O)OCCc1c[nH]c(=O)[nH]c1=O
Reactant: CO
Product: COCCc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
6.0 g of 5-(2-methylsulphonyloxyethyl)-uracil are suspended in 100 ml of absolute methanol and the suspension is heated to 120°-130° C. for one hour in a pressure vessel. After cooling to room temperature, the crystals obtained are filtered off and washed with methanol. 5-(2-Methoxyethyl)-uracil, melting point 232°-234° C., is obtained.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23](=[O:43])[N:24]([CH3:42])[C@@H:25]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:30]1[CH:29]=[CH:28][C:27]([C@H:25]([N:24]([CH3:42])[C:23](=[O:43])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:26])=[CH:32][CH:31]=1
Reactant: C[C@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 68.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one 1.4 g, 4.4 mmol) was reacted with (R)-tert-butylmethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (2.4 g, 6.6 mmol) to afford the desired product (1.4 g, 66%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:11][C:10]([CH2:9][CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCOc1ccc(CO)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[4-(hydroxymethyl)phenoxy]propionic acid (0.98 g) and potassium carbonate (0.9 g) in N,N-dimethylformamide (5 mL) was added benzyl bromide (0.65 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.1 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=2)[CH2:3]1.[OH:15][Li].O>OO>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH2:14])=[O:15])=[N:11][CH:12]=2)[CH2:3]1
Reactant: [Li]O
Reactant: N#Cc1ccc(N2CCC(O)C2)cn1
Agent: OO
Solvent: O
Product: NC(=O)c1ccc(N2CCC(O)C2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
A mixture of 5-(3-hydroxypyrrolidin-1-yl)picolinonitrile (2.7 g, 14.3 mmol) in H2O2 (30 mL) was added LiOH.H2O (1.8 g, 42.9 mmol) and the mixture was stirred at rt for 16 h. The precipitate was collected by filtration and the cake was washed with water (20 mL) to give the desired product (2.2 g, 74%) as a yellow solid. [LCMS: RtA=1.05 min, m/z 208.2 [M+H]+].
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:30][NH:31][S:32]([N:35]([CH2:41][C:42]([C:44]1[N:45]=[CH:46][N:47]2[CH:51]=[CH:50][S:49][C:48]=12)=[O:43])[S:36]([NH:39][CH3:40])(=[O:38])=[O:37])(=[O:34])=[O:33].[Cl-].[NH4+]>C1COCC1>[CH3:30][NH:31][S:32]([N:35]([CH2:41][C:42]([C:44]1[N:45]=[CH:46][N:47]2[CH:51]=[C:50]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:49][C:48]=12)=[O:43])[S:36]([NH:39][CH3:40])(=[O:37])=[O:38])(=[O:33])=[O:34]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CNS(=O)(=O)N(CC(=O)c1ncn2ccsc12)S(=O)(=O)NC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CN(S(=O)(=O)NC)S(=O)(=O)NC)c2s1
Reaction time: 0.5 h

Procedure:
Tri-n-butylstannyl chloride (0.962 ml) and 8.42 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were sequentially added at −73° C. in an argon atmosphere to a solution of 485 mg of 7-(N,N-dimethylaminosulfonylamino)acetyl-imidazo[5,1-b]thiazole in 18 ml of THF. The mixture was stirred at the same temperature for 30 min. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 427 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: NCCSCc1nccs1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
By the procedure of Example 8(i), 2-[(2-aminoethyl)-thiomethyl]thiazole (from the dihydrobromide, 4.0 g) is reacted with 1-nitro-2,2-bis methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 63°-64°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([O:20][CH3:21])[N:15]=[C:14]([O:22][CH3:23])[N:13]=2)C#N)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].CN(C=[O:30])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([O:20][CH3:21])[N:15]=[C:14]([O:22][CH3:23])[N:13]=2)=[O:30])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CCc1c(OC)nc(OC)nc1C(C#N)c1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a stirred solution of (62) (1.97 g, 5.59 mmol) in anhydrous DMF (25 ml) under nitrogen atmosphere, was added 60% sodium hydride (224 mg, 5.59 mmol). After 10 min., oxygen was bubbled into the reaction mixture for 4 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, ether:hexanes (1:30)) to afford 1.37 g (72%) of the title compound as a white solid. m.p. 118-119° C.; 1H NMR (200 MHz, CDCl3) δ 1.09 (3H, t, J=7.4 Hz), 2.46 (2H, q, J=7.4 Hz), 3.95 (3H, s), 4.08 (3H, s), 7.58 (1H, t, J=1.8 Hz), 7.56 (2H, d, J=1.8 Hz).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[C:6](Cl)(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C:6]([O:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=C(O)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)COC(=O)C=Cc1ccccc1
Yield: 25.2 %

Procedure:
To a solution of glycolic acid (15.2 g.) in pyridine (100ml.) was added cinnamoyl chloride (33.4 g.) with stirring under cooling. The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure at 50° to 60° C. The residue was adjusted to pH 1 with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and a sodium chloride aqueous solution, in turn and concentrated under reduced pressure to give colorless crystals (45 g.). These crystals were dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3 to 3.5 with aqueous hydrochloric acid and extracted with ether. The extract was treated with a conventional manner to give crude product (16.5 g.). The product was recrystallized from benzene to give a product of 2-cinnamoyloxyacetic acid (10.4 g.), m.p. 116° to 121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:16]I>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1

Procedure:
A mixture of 1 g (4 mmol) 2-Chloro-5-sulfino-benzoic acid in 20 ml methanol and 20 ml water was treated with 10N NaOH to pH=9 before adding 1.7 g (12 mmol) methyliodide. The mixture was heated for 48 h to 80° C. with occasional addition of NaOH to maintain pH=9. After removal of all volatiles HCl conc. was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was taken up in methanol and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 323 mg (34%) of the title compound. MS (m/e): 233.0 (M−H, 100%)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CN
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CNCC(=O)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.1 g, 0.85 mmol) in THF (10 mL) diisopropyl ethyl amine (81 mg, 0.62 mmol) was added at 0° C. followed by methyl amine solution (30% solution, 10 mL). The reaction mixture was allowed to stir for overnight at room temperature. The reaction mixture was poured into a large volume of water (50 mL) and the solution was extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain the title compound (20.0 mg, 22.90% yield) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:38])[CH2:21][NH:22]C(=O)[C@H](CC(C)C)NC(OC(C)(C)C)=O)=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(COC(N(CC(NCCNC(=O)CNC(OC(C)(C)C)=O)=O)C)=O)C=CC=CC=1.[ClH:69].O>ClCCl>[ClH:69].[C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:38])[CH2:21][NH2:22])=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCCNC(=O)CN(C)C(=O)OCc1ccccc1
Agent: CN(CC(=O)NCCNC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(CC(=O)NCCNC(=O)CN)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-(N-(1,1-Dimethylethoxycarbonyl)leucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide. N-(1,1-Dimethylethoxycarbonyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide (5.22 g, 8 mmol) was treated with excess hydrogen chloride in dichloromethane (50 mL) for 1 h. Water (50 mL) was added and the mixture was stirred vigorously for 15 min. The solvent and excess reagent were evaporated from the aqueous layer under reduced pressure to give crude glycine N-(2 -(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide hydrochloride as a white solid. This material was stirred with N,N-diisopropylethylamine (3.231 g, 25 mmol) and N-(1,1-dimethylethoxycarbonyl)leucine 2,4,5-trichlorophenyl ester (3.19 g, 7.8 mmol) (Example II, Intermediate A) in dimethylformamide (30 mL) for 3 d. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and was washed with aqueous sodium hydroxide (5%), aqueous sulphuric acid (10%) and water and was dried wilh anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave N-(N-(1,1-dimethylethoxycarbonyl)leucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide (3.26 g, 78%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].S(OOS([O-])(=O)=O)([O-])(=O)=[O:13].[K+].[K+].S(=O)(=O)(O)O>O>[O:5]=[C:4]1[C:2](=[O:3])[NH:1][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:13]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2ccccc2oc1=O
Reaction time: 24 h

Procedure:
14.7 parts of isatin are introduced into a suspension of 29 parts of potassium peroxydisulfate in 280 parts of 30% strength sulfuric acid at room temperature. The reaction mixture is then stirred for 24 hours without cooling, after which it is poured into water. The product is filtered off and dried, giving 11 parts of 2,3-dioxo-1,4-benzoxazine, of melting point 279°-283° C. (with decomposition).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].[OH-].[Li+].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccccn2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A solution of {5-fluoro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}acetic acid methyl ester (0.050 g) in tetrahydrofuran (0.30 mL) was treated with 1.0 M aqueous lithium hydroxide solution (1.0 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was treated with 5.0 M aqueous sodium hydroxide solution (1.0 mL) and stirred at room temperature for 3 hours and then at 40° C. overnight. The mixture was acidified by the addition of aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 19:1 by volume) to afford the title compound as a yellow solid (0.020 g).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][CH2:10][C@@H:11]([C:33]([OH:35])=[O:34])[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:16][C:15]=1[Cl:31])=[O:8].BrC1SC(C(NC[C@@H](C(O)=O)NC(=O)C2C=CC(C(NCC3C=CC=C(O)C=3)=O)=CC=2Cl)=O)=CC=1.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1Cl)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC(Cl)=CC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC(Br)=C(Br)C=1)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1C)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC(C)=CC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1C=CSC=1)=O)=O>>[Cl:31][C:15]1[CH:16]=[C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C@H:11]([C:33]([OH:35])=[O:34])[CH2:10][NH:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][CH:2]=1)=[O:8])=[O:32]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2sccc2Br)C(=O)O)c(Cl)c1
Agent: Cc1ccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Agent: Cc1ccsc1C(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(Br)c(Br)s2)C(=O)O)c(Cl)c1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1

Procedure:
3-(3-bromothiophene-2-carbonyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; 3-(5-bromothiophene-2-carbonyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3-chlorothiophene-2-carbonyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(5-chlorothiophene-2-carbonyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(4,5-dibromothiophene-2-carbonyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3-methylthiophene-2-carbonyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(5-methylthiophene-2-carbonyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-3-carbonyl)]amino-L-alanine).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@H:9]([NH:18]C(O[C@H](C2C=CC=CC=2)C)=O)[CH2:8][C@@H:7]1[CH2:30][CH3:31])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@H:9]([NH2:18])[CH2:8][C@@H:7]1[CH2:30][CH3:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@H](NC(=O)O[C@@H](C)c2ccccc2)C[C@@H]1CC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@H](N)C[C@@H]1CC
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Ten % palladium/carbon (100 mg) is added to a solution (10 ml) of (2S,4R)-2-ethyl-6-methoxy-4-[(S)-1-phenylethoxycarbonylamino]-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1.00 g) in ethanol, and the mixture is stirred for 3 hours under hydrogen. Palladium/carbon is removed by filtration, and the filtrate is concentrated under reduced pressure to give (2S,4R)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (619 mg). MS (m/z): 280 [M+H]+