Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:28])[NH:12][C:13](=[O:27])[C:14]=2[C:15]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=[CH:24]3)S[CH2:19][CH2:18][N:17]4[CH:16]=2)=[CH:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:40](=[O:43])(O)[O-:41].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:28])[NH:12][C:13](=[O:27])[C:14]=2[C:15]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=[CH:24]3)[S:40](=[O:43])(=[O:41])[CH2:19][CH2:18][N:17]4[CH:16]=2)=[CH:2]1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)SCC3)=C1c1c[nH]c2ccccc12
Reactant: O=S([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)S(=O)(=O)CC3)=C1c1c[nH]c2ccccc12
Reaction time: 24 h
Yield: 23.8 %

Procedure:
To a solution of 3-(1H-indol-3-yl)-4-(4,5-dihydro-3H-5-thia-2a-aza-acenaphthylen-1-yl)pyrrole-2,5-dione (0.50 g, 1.3 mmol) in dichloromethane was added meta-chloroperbenzoic acid (0.671 g, 3.89 mmol) at 0° C. After 24 hrs at room temperature, a saturated solution of sodium bisulfite and sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was subjected to silica gel chromatography, eluting with ethyl acetate/hexane (4:1) to give 0.120 g (23.8%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CCOC(C)=O.O>C1COCC1>[CH3:16][S:17]([O:15][CH:12]1[CH2:13][CH2:14][N:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][CH2:11]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)ON1CCC(O)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)ON1CCC(OS(C)(=O)=O)CC1
Reaction time: 2.5 h
Yield: 87.9 %

Procedure:
To a solution of 1-[(tert-butoxycarbonyl)oxy]piperidin-4-ol (10.0 g, 49.7 mmol) in THF (200 mL), were added TEA (20.7 mL, 149 mmol) and methanesulfonyl chloride (7.69 mL, 99.4 mmol) at 0° C. The mixture was stirred for 2.5 h at the same temperature. To the mixture was added EtOAc (100 mL) and water (100 mL) and then organic layer has been separated. The aqueous layer has been extracted with EtOAc (50 mL) and the combined organic layer was washed with brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane 20/80→350/50). Concentration of appropriate fractions afforded crude product, which was washed with a 1:1 mixture of diethyl ether and hexane (50 mL) to give title compound (12.9 g, 92%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C(O)(C(F)(F)F)=O>>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2CC(O)C3(CCNCC3)C2=O)COC1=O

Procedure:
The title compounds were prepared from Isomers A and B of tert-Butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate, respectively, using TFA in a similar fashion as described previously for I-19. Isomer A: LC/MS: [(M+1)]+=267; Isomer B: LC/MS: [(M+1)]+=267.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28]>CN(C=O)C.O>[Si:6]([O:29][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C#CCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 1265.9 %

Procedure:
Imidazole (9.29 g (136 mmol) was dissolved in 50 ml of DMF under nitrogen with stirring. To this solution was added 18.75 g (17.74 mmol) of t-butyldiphenylsilyl chloride and 5.27 g (5.55 mmol) of 4-pentyn-1-ol and the mixture was stirred at room temperature for 2 h. The mixture was carefully diluted with 300 ml of water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 22.66 g of a yellow oil which was purified by passing through 150 g pad of silica gel eluting with hexane and 3% ethyl acetate in hexane affording 17.56 g (86.8%) of the title compound as a clear oil.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (359 mg, 0.79 mmol) in 1,4-dioxane (10.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (9.8 mL, 39 mmol) at room temperature. The reaction mixture was stirred for 5 hours. The solvent was then removed by reduced pressure to afford the crude product (3R)-3-(cyclopentyl methyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (314 mg, 100%), which was used directly in the next step. MS: 401 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Cc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Methylphenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Br[CH:2]([CH2:10]Br)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[SH:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[S:12]1[CH2:13][CH2:14][NH:15][CH:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:10]1
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)C(Br)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CSCCN1

Procedure:
Preferably, t-butyl 2,3-dibromopropionate prepared according to J. Perkin Trans I, p. 1321 (1973) is treated with 2-mercaptoethylamine and triethylamine in a suitable solvent, such as a mixture of chloroform and benzene, to provide t-butyl tetrahydro-2H-1,4-thiazine-3-carboxylate, which upon reaction with a compound of the formula V under suitable conditions, such as in the presence of triethylamine in dichloromethane solution at 25° C., provides compounds of the formula II-c. Oxidation of this material with a suitable oxidizer, such as sodium perborate or m-chloroperbenzoic acid, provides the corresponding sulfoxide, preferably as a single diastereomer.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:15]>C1COCC1.C(O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:15])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: N
Solvent: C1CCOC1
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a solution of 2-(trifluoromethyl)benzenesulfonyl chloride (5 g; 20.44 mmol; 1.00 eq.) in anhydrous THF (5.00 ml) was added a solution of 71 ml Ammonia in Ethanol 2M under nitrogen at room temperature. The reaction mixture was shaken for 20 h at room temperature. The solvent was evaporated and the residue redissolved in EtOAc (150 mL) and then washed with NH4Cl saturated aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and the solvent evaporated to give the pure 2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (4.6 g, 89% yield, 98.6% HPLC purity). This compound was utilized as such for the next reaction.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[Cl:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CNc1ccccc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
4.07 g of sodium triacetoxyborohydride (19.3 mmol) was added to a solution of 3.00 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (16.0 mmol), 2.04 g of 2-chloroaniline (16.0 mmol) and 0.92 ml of acetic acid (16.0 mmol) in methylene chloride (160 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.49 g of the title compound (yield: 73%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:22]>>[C:1]1([S:7]([C:10]2[CH:11]=[N:12][N:13]3[C:18]([Cl:22])=[CH:17][C:16]([CH3:19])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccn2ncc(S(=O)(=O)c3ccccc3)c2n1
Product: Cc1cc(Cl)n2ncc(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
A suspension of 0.91 g (3.14 mmol) of 3-benzenesulphonyl-5-methyl-pyrazolo[1,5-a]pyrimidine in 15 ml of POCl3 was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 30 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 20 ml of CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 19:1) of the residue yielded 0.84 g (87%) of 3-benzenesulphonyl-7-chloro-5-methyl-pyrazolo[1,5-a]pyrimidine as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:20][CH:19]3[O:21][CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18]3)[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH:19]12[O:21][CH:15]([CH2:16][NH:17][CH2:18]1)[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:20]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCCCN2CC3CNCC(C2)O3)cc1
Reaction time: 3 h
Yield: 102.7 %

Procedure:
A 2 L three-necked flask was equipped with a magnetic stirrer, a thermometer and an addition funnel. The flask was charged with tert-butyl 7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (34 g, 88 mmol, from step (iv) above) and dichloromethane (440 mL). Trifluoroacetic acid (132 mL) was added slowly at room temperature. The solution was stirred for three hours at which point TLC analysis showed complete consumption of starting material. The contents were transferred to a single-necked flask and concentrated under vacuum. The residue was dissolved in dichloromethane (500 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over magnesium sulfate and concentrated under vacuum to afford 25.8 g (100% yield) of sub-title compound as an off-white solid. The crude material was used in the next step without farther purification.
Reaction SMILES: NC1C=CC(I)=CN=1.C(NC1C=CC(S)=CC=1)(=O)C.C[O-].[Na+].C(NC1C=CC([C:33]2([S:40][C:41]3[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:50])[CH3:49])=[CH:43][CH:42]=3)[CH:38]=[N:37][C:36]([NH2:39])=[CH:35][CH2:34]2)=CC=1)(=O)C>[Cu]>[C:48]([NH:47][C:44]1[CH:43]=[CH:42][C:41]([S:40][C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)=[CH:46][CH:45]=1)(=[O:50])[CH3:49]
Reactant: CC(=O)Nc1ccc(SC2(c3ccc(NC(C)=O)cc3)C=NC(N)=CC2)cc1
Agent: [Cu]
Agent: CC(=O)Nc1ccc(S)cc1
Agent: C[O-]
Product: CC(=O)Nc1ccc(Sc2ccc(N)nc2)cc1

Procedure:
5.5 G. (0.25 mole) of 2-amino-5-iodopyridine, 5.02 g. (0.030 mole) of 4-acetamidothiophenol and 1.6 g. of sodium methoxide 800 mg. of copper under the conditions as in Example 2 (A) one obtains 5.8 g. of 5(p-acetamidophenyl) 5-(p-acetamidophenylthio)2-amino pyridine m.p. 178°-179° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([OH:39])=[CH:37][CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:39][C:38]3[CH:40]=[CH:41][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of hydroquinone monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 16 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 210°-211°.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:42])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1.O>C(O)(=O)C>[CH3:40][N:36]1[C:37]2[C:32](=[CH:31][C:30]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([OH:42])=[O:6])=[CH:9][CH:10]=3)[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]1=[O:41]
Reactant: COC(=O)c1ccc(CN(CCCCCOc2ccc3c(ccc(=O)n3C)c2)CCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A 1N-sodium hydroxide aqueous solution (0.72 ml) was added to a methanol solution (2 ml) of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (153 mg). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, and acetic acid was added for neutralization. The mixture was extracted using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. Diisopropyl ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (115 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[F:18][C:19]([F:36])([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][NH:32][C:31]2=[O:35])=[CH:26][CH:25]=1)[CH:20]([F:22])[F:21].[H-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:19]([F:36])([F:18])[CH:20]([F:22])[F:21])=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Reaction time: 20 h
Yield: 8.2 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.5 g), 2.66 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 0.386 g of 60% sodium hydride in oil were added to 25 ml of N,N-dimethylformamide. The mixture was stirred at 80° C. for 20 hours. After cooling, the reaction mixture was added to 100 ml of water and extracted with ethyl acetate (50 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) to give 0.27 g of 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH2:19]([O:18][C:16]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A 15.0 g sample of D-phenylalanine was dissolved in 45 ml of aqueous solution containing 7.26 g of 50% sodium hydroxide. This solution was stirred at 0°-10° C. as 16.3 g of benzyl chloroformate was added rapidly in portions. The resulting reaction was mildly exothermic, and shortly after addition, solids precipitated. An additional 45 ml of water and 3.63 g of 50% sodium hydroxide were added, causing most of the solids to redissolve. The reaction mixture was stirred for 20 minutes and then acidified with 6N hydrochloric acid. The resulting solids were filtered, washed with water and then with hexane, and dried by suction and then under vacuum to give 47 g of white solids. These solids dissolved in ether were washed twice with 1N hydrochloric acid and then with water, dried over MgSO4 and stripped to 35° C. at 2.5 mm Hg to give 27.7 g of the desired product as a colorless oil.
Reaction SMILES: [H][H].[O:3]=[C:4]([O-:14])[C:5]([CH2:7][C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])=[O:6].[K+:15]>>[C:4](=[O:14])=[O:3].[O:3]=[C:4]([O-:14])[C:5]([CH2:7][C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])=[O:6].[K+:15]
Reactant: [H][H]
Agent: O=C([O-])C(=O)C[C@H](O)[C@H](O)CO
Agent: [K+]
Product: O=C=O

Procedure:
0.5 ml of a 31% hydrogen peroxyde solution were added to 5 ml of a 1M potassium 2-dehydro-3-deoxy-D-gluconate (KDG) solution at 25° C. The progression of KDG decarboxylation was followed both by the observation of bubbles resulting from the release of carbon dioxide and by the disappearance of KDG using the thin layer chromatography protocol described in example 2. Typically, after a 3 h period of reaction the concentration of residual KDG was less than 10 mM.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][C:17]1[CH:50]=[CH:49][C:20]([CH2:21][NH:22][C:23]2[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:26]=[C:25]([NH:35][C:36]3[CH:48]=[CH:47][C:39]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:38][CH:37]=3)[N:24]=2)=[CH:19][CH:18]=1)=[O:15])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]2[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:32])[F:33])[N:26]=[C:25]([NH:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([OH:42])=[O:41])=[CH:47][CH:48]=3)[N:24]=2)=[CH:49][CH:50]=1)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Nc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)NCC(=O)Nc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
tert-butyl 4-(4-(4-(2-(2-(tert-butoxycarbonylamino)acetamido)acetamido)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate and 4 N HCl in Dioxane (2 mL, 8.00 mmol) were stirred for 1 h then concentrated under vacuum to give 4-(4-(4-(2-(2-aminoacetamido)acetamido)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (112 mg) which was carried to the next step without purification.