Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]([CH2:29][C:30]([C:32]1[C:37]([O:38]C)=[CH:36][CH:35]=[CH:34][C:33]=1[O:40][CH3:41])=[O:31])[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13]=1[C:14]([F:17])([F:16])[F:15])=[O:8].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]([CH2:29][C:30]([C:32]1[C:33]([O:40][CH3:41])=[CH:34][CH:35]=[CH:36][C:37]=1[OH:38])=[O:31])[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13]=1[C:14]([F:15])([F:17])[F:16])=[O:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(OC)cccc3OC)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(O)cccc3OC)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Reaction time: 16 h

Procedure:
To a stirred solution of compound 7-3 (50 mg, 0.07 mmol) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 1.5 mL, 1.4 mmol) at room temperature and the mixture was stirred for 16 h. Solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 7-4 (32 mg, 65%) as a brown color gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][N:5]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:7]=1.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:44])[CH2:4][N:5]([C:6]1[CH:7]=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:9]=[C:10]([OH:12])[CH:11]=1)[CH2:39][C:40]([O:42][CH3:43])=[O:41]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 23 h
Yield: 96.5 %

Procedure:
A mixture of 15.55 g of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy) phenyl]glycine methyl ester and 3.0 g of 10% palladium on carbon in 500 mlof THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 23 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 12.8 g (97% yield, 96°-98°) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#Cc1cccc(NC(=O)CCl)c1
Solvent: CCOCC
Product: N#Cc1cccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-cyano-phenyl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 88-90° C. (diethylether)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH2:21][C:20]1=[O:28])[CH2:5][CH2:6][CH3:7]>[OH-].[Na+].CO>[C:15]([C:13]1[CH:12]=[CH:11][C:10]([N:19]2[C:23]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH2:21][C:20]2=[O:28])=[C:9]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[CH:14]=1)([OH:17])=[O:16]
Reactant: CCCC(CCC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(CCC)Nc1cc(C(=O)O)ccc1N1C(=O)CCC1(CO)CO
Reaction time: 12 h
Yield: 92.5 %

Procedure:
A suspension of the above ester (0.08 g, 0.2 mmol) in 1 N sodium hydroxide (1.5 mL) and methanol (1 mL) was stirred at ambient tmperature for 12 h. Upon acidification of the reaction mixture with glacial acetic acid, a solid precipitated. The solid was collected by filtration and dried to give 0.07 g (90%) of the title compound, mp 227-229° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[CH:36]=4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:18])[CH3:19]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M105) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (161 mg, 48%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[CH:18]=1)(=[NH:4])[NH2:3].[C:19](Cl)(=[O:22])[O:20][CH3:21].[OH-].[Na+].Cl>O.O1CCCC1.C(Cl)Cl>[CH3:21][O:20][C:19]([NH:3][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:18]=1)=[NH:4])=[O:22]
Reactant: CCOC(=O)c1cc2cc(C(=N)N)ccc2o1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc2oc(C(=O)O)cc2c1
Reaction time: 0.17 h
Yield: 187.6 %

Procedure:
Methylene chloride (2 ml) was added to ethyl 5-amidino-2-benzofurancarboxylate hydrochloride (100 mg, 0.372 mmol), and methyl chlorocarbonate (30 μl, 0.391 mmol) and then, a 0.2N aqueous sodium hydroxide solution (0.391 ml, 0.782 mmol) was added at room temperature, which was followed by vigorous stirring for 10 minutes. Methylene chloride (15 ml) was added to the reaction mixture. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 88.0 mg of ethyl 5-(methoxycarbonylamidino)-2-benzofurancarboxylic as a colorless solid (82%). Tetrahydrofuran (2 ml), water (2 ml) and a 1N aqueous sodium hydroxide solution (2 ml, 2 mmol) were added to the compound (73.0 mg, 0.252 mmol), and the mixture was stirred at room temperature for one hour. 1N Hydrochloric acid was added to the reaction mixture to adjust its pH to 2-3, and low boiling matters were distilled away under reduced pressure to give 183 mg of 5-(methoxycarbonylamidino)-2-benzofurancarboxylic acid as a yellow solid (inclusive of sodium chloride).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[CH:4]=1)[CH3:2].S(OC)(O[CH3:27])(=O)=O>>[CH2:1]([C:3]1[N:8]([CH3:27])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Product: CCc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2,4 (1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 72°-74° C.;
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([Cl:19])=[C:11]2[Cl:20])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:23](=O)([O-])[O-:24].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C(P(C(C)(C)C)C1C(OC)=CC=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[Cl:20][C:11]1[N:10]([C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([O:24][CH3:23])[C:3]=2[O:21][CH3:22])[C:18]2[C:13]([C:12]=1[Cl:19])=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(Br)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: COc1ccc(C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Temperature: 110 °C
Yield: 66 %

Procedure:
6-bromo-4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-pyridazin-3-one (0.200 g, 0.496 mmol), Pd2Cl2(allyl)2 (2.7 mg, 0.00744 mmol), ditert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (11.6 mg, 0.0248 mmol) and dicesium carbonate (0.243 g, 0.744 mmol) are suspended in toluene (3 mL) and methanol (60 μL). The resulting reaction mixture is heated under microwave irradiation to 110° C. for 20 min. The resulting reaction mixture is filtered, washing with EtOAc and concentrated under reduced pressure onto silica. Purification by flash chromatography (combiflash, 0 to 30% EtOAc/isohexane) afforded the desired product 4-(2,3-dichloroindol-1-yl)-5,6-dimethoxy-2-methyl-pyridazin-3-one (0.116 g, 0.3275 mmol, 66% yield) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:10]([C:9]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)O
Reactant: Nc1ccncc1N
Product: CCCCc1nc2cnccc2[nH]1
Temperature: 70 °C
Yield: 99.6 %

Procedure:
A mixture of 3 g of 3,4-diamino-pyridine and 8.28 g of valeric acid was heated to 70° C. for 18 hours and the reaction medium was chromatographed on silica (eluant: ethyl acetatemethanol (8-2)) to obtain 4.8 g of the expected product which was used as is for the following step.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:23]([NH2:25])[CH3:24].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:7]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]1[C:20](=[O:22])[NH:25][CH2:23][CH3:24])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
15.25 ml of triethylamine and subsequently a solution of 10.48 ml of ethyl chloroformate in 50 ml of dry tetrahydrofuran were added at -25° C. to a solution of 23.13 g of (2S, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 350 ml of dry tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. At the end of this time, a 70% by volume aqueous ethylamine solution was added at -22° C., the reaction temperature was allowed to rise gradually and the reaction finished when the temperature reached 10° C. The reaction mixture was then mixed with a small amount of an aqueous solution of sodium chloride, after which it was extracted thrice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 23.60 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=[N:27][OH:28])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2c(c1)C(=O)CCC2C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc2c(c1)C(=NO)CCC2C1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 5.20 grams (21.49 mmol) 4-cyclohexyl 7-methyl-1,2,3,4-tetrahydronaphth-1-one, 54 mL methanol, 3.25 grams (32.23 mmol) triethylamine, and 2.22 grams (32.23 mmol) hydroxylamine hydrochloride. The reaction was stirred at room temperature for 1.5 days, evaporated, partitioned between ethyl acetate and water, and the aqueous layer extracted with fresh ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated to an oil, which was used directly.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:18](#[N:22])[CH2:19][C:20]#[N:21].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:19]([C:18]#[N:22])[C:20]#[N:21])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(C=C(C#N)C#N)ccc21
Reaction time: 0.5 h

Procedure:
About 11.1 grams (0.05 moles) N-ethyl carbazole-3-carboxaldehyde, about 3.1 grams (0.05 moles) malononitrile, about 1 milliliter glacial acetic acid, about 0.35 grams ammonium acetate and about 40 milliliters benzene are heated to boiling under reflux conditions for about 30 minutes. The liquid portion of this mixture is separated from the brown colored solution by rotary evaporation, the solid residues twice recrystallized with glacial acetic acid washed with ethanol and dried in a vacuum oven. Yield: 7.0 grams of bright yellow needle like crystals m.p. 164°-165° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH2:27]([O:29][C:30]([O:32][CH:33](Cl)[CH3:34])=[O:31])[CH3:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:28][CH2:27][O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: CCOC(=O)OC(C)Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (11) (1.0 g, 2.4 mmol) dissolved in 15 mL of anhydrous toluene was reacted with 1.1 g (7.3 mmol) of commercially available 1-chloroethyl ethoxyformate in the presence of 0.81 g (2.9 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.77 g of a mixture of the title compound (36a) and (3R)-4,4-dimethyl-3-[(4-methoxyphenyl)methoxy]-3,4,5-trihydrofuran-2-one. MS (ESI) m/z 546.99 (M+Na)+.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:89])[C@H:83]([CH2:85][C:86]([OH:88])=[O:87])O>C1COCC1>[CH3:35][CH:34]([CH3:36])[CH2:33][C@@H:32]([B:4]1[O:5][C@@H:83]([CH2:85][C:86]([OH:88])=[O:87])[C:82](=[O:89])[O:3]1)[NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1)=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.500 g, 0.455 mmol) and L-malic acid (213.6 mg, 0.55 mmol) were mixed in THF (5 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 1 h. The slurry was filtered to collect solid 2-((S)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.625 g, 95%). MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O7, 483.2051. found, 483.2.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[C:14]([F:15])=[CH:13][C:12]([N:16]4[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]4=[O:26])=[CH:11][C:10]=3[F:27])[CH2:5][CH2:4]2)[CH2:2]1.[N-:28]=[N+:29]=[N-:30].[Na+].C(O)(=O)C>CN(C)C=O>[N:28]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:5][CH2:4]1)=[N+:29]=[N-:30]
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC(O)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Yield: 65 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with sodium azide (2.10 mmol) and glacial acetic acid (7.0 mmol) in dimethylformamide (15 ml) at a temperature 40° C. for 14 hours and by purifying the compound by silica gel column chromatography in 65% yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18]>C(O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[S:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)CCCSc1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(SCCCC(=O)O)cc2ccccc21

Procedure:
70 ml of normal sodium hydroxide are added to a solution of 18.30 g of ethyl 4-(1-methyl-2-indolylthio)butanoate, obtained in the preceding stage, in 250 ml of ethanol. After 1 hour of heating under reflux, the reaction medium is evaporated and the residue is taken up with water. The aqueous phase is washed with ethyl acetate and acidified with aqueous hydrochloric acid solution. The precipitate is drained, washed with water, dried and recrystallized in ethanol.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([OH:10])[C:6]([CH3:9])([CH3:8])[CH3:7].CN1C=CN=C1>>[C:1]([O:10][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)CO
Reactant: CC(=O)Cl
Agent: Cn1ccnc1
Product: CC(=O)OCC(C)(C)C
Temperature: 20 °C
Yield: 86 %

Procedure:
6.47 g (82.5 mmol) of acetyl chloride were added dropwise to a solution of 6.61 g (75.0 mmol) of neopentyl alcohol (2,2-dimethyl-1-propanol) and 6.76 g (82.5 mmol) of 1-methylimidazole while stirring at 20° C. The reaction mixture was stirred for a further 30 minutes and subsequently heated to 75° C. This resulted in the suspension initially formed being converted into a liquid two-phase mixture. The upper phase was separated off to give 8.40 g (theory: 9.76 g) of neopentyl acetate as a colorless oil having a purity of 98% (GC).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2>ClCCCl.CC#N.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=[O:1]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CO)ccc43)nn2)C(N)=O)cc1
Agent: O=[Mn]=O
Solvent: ClCCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-3-(1-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.66 g, 1.4 mmol) in DCE/MeCN (1:1, 30 mL) was added MnO2. The reaction mixture was stirred overnight at RT. The solid was removed by filtration, and the filtrate was concentrated to give a tan solid. MS (m/z): 468.4 (m+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:14]([C:28]([F:31])([F:30])[F:29])=[CH:13][C:12]=1[NH2:32])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl-].C([O:43][C:44](=O)[C:45](O)=[O:46])C.Cl.C([NH+](CC)CC)C>O1CCCC1>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:11]2[C:12](=[CH:13][C:14]([C:28]([F:30])([F:31])[F:29])=[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:16]=2)[NH:32][C:44](=[O:43])[C:45]1=[O:46])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOC(=O)C(=O)O
Reactant: CCOP(=O)(CNc1cc(OCCOc2ccc(Cl)cc2)c(C(F)(F)F)cc1N)OCC
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(OCCOc3ccc(Cl)cc3)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 g of N-[2-amino-4-trifluoromethyl-5-(2(-4-chlorophenoxy)ethoxy)phenyl]-aminomethanephosphonic acid diethyl ester is introduced in 60 ml of tetrahydrofuran with 733 mg of triethylamine and mixed drop by drop at room temperature with a solution of 719 mg (0.59 ml) of oxalic acid ethyl ester chloride in 15 ml of tetrahydrofuran. Then, it is stirred for 2 hours at room temperature. After triethylammonium hydrochloride is suctioned out, the filtrate is concentrated by evaporation. The residue is taken up in 25 ml of ethanol and 25 ml of 1N hydrochloric acid and heated for 2 hours to a bath temperature of 120° C. After the ethanol is distilled off, it is diluted with water to 50 ml, and extracted three times with 50 ml of ethyl acetate each. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 810 mg of [(6-trifluoromethyl-7-(2(-4-chlorophenoxy)ethoxy)-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl]methanephosphonic acid diethyl ester is obtained.