Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([OH:21])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of 1-(2-tetrahydropyranyloxy)-4 -hydroxy-5-(4-fluorophenoxy)-trans-2-pentene (23.6 g., 0.08 mole), acetic anhydride (9.2 g., 0.09 mole), and pyridine (7.9 g., 0.1 mole) is heated at 55°-60° for 4 hours and then at 95° for an additional 4 hours. The solution is cooled, diluted with ether and washed with ice-cold saturated sodium carbonate solution, ice water (3×) and brine, and dried over sodium sulfate. Removal of solvent under vacuum leaves the title compound as a residual orange oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:13][CH2:14][C:15]#[N:16])[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)#[N:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[Cl-:24].[NH2:17][C:18]1[C:23]2[C:22](=[N+:5]([C:6]3[CH:12]=[CH:11][CH:9]=[CH:8][CH:7]=3)[C:8]3[C:9]([N:10]=2)=[CH:11][CH:12]=[C:6]([N:5]([CH2:4][CH2:3][C:1]#[N:2])[CH2:13][CH2:14][C:15]#[N:16])[CH:7]=3)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: N#CCCN(CCC#N)c1ccc(N)cc1
Reactant: Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: N#CCCN(CCC#N)c1ccc2nc3c(N)cccc3[n+](-c3ccccc3)c2c1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 3-liter round-bottomed flask fitted with a mechanical stirrer was loaded with 16.6 g (0.066 mole) of 4-(bis-(2-cyanoethyl)amino) aniline in 800 ml of distilled water. A 10% excess of aniline (13.56 g, 0.1456 mole) and 200 ml of distilled water were added to the mixture. The mixture was cooled to 0° C. in an ice bath, and 10 g concentrated hydrochloric acid in 25 ml of water were added. Then 6.31 g (0.0883 mole) of sodium dichromate in 25 ml of water was added. The temperature rose to 7° C. Stirring was continued as 9 ml of concentrated hydrochloric acid in 25 ml of distilled water was added over a period of two hours. After 16 hours the temperature had risen to 20° C. The mixture was heated under reflux for 4 hours and then filtered hot. The filter cake was washed with 1.5 liters of boiling water. The combined filtrates were concentrated to 1.4 liters and then heated to 75° C. as 200 g of sodium chloride were added.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5][N:4]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CS(C)=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 2.00 g is suspended in dimethyl sulfoxide 10 ml, and the suspension is treated with a 10% aqueous sodium hydroxide solution 10 ml. The reaction mixture is still in suspension even 6 hours later. After addition of dimethyl sulfoxide 5 ml the mixture is stirred at room temperature over night. The resulting clear reaction solution is acidified with citric acid. The excess water (about 50 ml) is added thereto and resulting precipitate is filtered, washed with isopropylalcohol and then isopropyl ether, and concentrated in vacuo to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a pale yellow impalpable powder, 1.864 g.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[NH2:36].NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:32][C:33]1[CH:34]=[C:35]([NH:36][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]3[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=3)[CH:4]=2)[CH:37]=[CH:38][C:39]=1[CH2:40][N:41]1[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]1
Reactant: CN1CCN(Cc2ccc(N)cc2Cl)CC1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cncn1C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1C#Cc1cncn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-methyl-3-[(1-methyl-1H-imidazol-5-yl)ethynyl]benzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-Chloro-4-((4-methylpiperazin-1-yl)methyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled. e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cccc(O)c1

Procedure:
A mixture of resorcinol (11.0 g), methyl 2-bromopropanoate (20 g), potassium carbonate (27.6 g) and methyl ethyl ketone (120 mL) was heated under reflux for 5 hours. The reaction mixture was filtered, evaporated and the residue was separated by chromatography. Elution with 1:3 ethyl acetate/hexane afforded the desired product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH2:54][CH3:55])=[CH:50][CH:51]=3)[CH2:46][CH2:45][NH:44]2)=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36].[C:56]([O:60][C:61](=[O:70])[CH2:62][C@@H:63]1[CH2:66][C@H:65]([C:67](O)=[O:68])[CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH2:54][CH3:55])=[CH:50][CH:51]=3)[CH2:46][CH2:45][N:44]2[C:67]([C@@H:65]2[CH2:64][C@H:63]([CH2:62][C:61]([O:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:70])[CH2:66]2)=[O:68])=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:37])([CH3:38])[CH2:34][O:35][CH3:36]
Reactant: CCOc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (113 mg, 0.30 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (123 mg, 0.27 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.7 mg, 0.30 mmol) and DIEA (0.107 mL, 0.59 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl (cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate (166 mg, 0.270 mmol, 100%).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[C:5]1(=O)CCCC[CH2:6]1.Cl.[OH:13][C@H:14]1[CH2:31][C@@:30]2([CH3:32])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[C@H:28]([NH:33][CH2:34][CH2:35][CH:36](C)[CH3:37])[CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:39]([OH:41])=[O:40])[CH2:16][C@@H:15]1[OH:42]>C(O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[CH:34]1([NH:33][C@@H:28]2[CH2:27][C@@:25]3([CH3:26])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C:39]([O:41][CH3:1])=[O:40])[C@H:20]3[C@H:29]2[C@:30]2([CH3:32])[C@@H:17]([CH2:18][CH2:19]3)[CH2:16][C@H:15]([OH:42])[C@@H:14]([OH:13])[CH2:31]2)[CH2:6][CH2:5][CH2:37][CH2:36][CH2:35]1
Reactant: [BH3-]C#N
Reactant: O=C1CCCCC1
Reactant: CC(C)CCN[C@@H]1C[C@]2(C)[C@@H](C(=O)O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](O)C[C@]3(C)[C@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 24 h

Procedure:
Sodium cyanoborohydride (2.0 g) and cyclohexanone (2.0 ml) were added to a solution of Intermediate 2 (2.0 g) in ethanol (30 ml) and the mixture was stirred for 24 h. The mixture was diluted with NaHCO3 solution and extracted with ethyl acetate (3×). The extract was washed with water, dried and evaporated to give a solid. This was dissolved in ethyl acetate and extracted with dilute hydrochloric acid (3×) and water (2×). These extracts were brought to pH 10 with 0.88 NH3 solution and then extracted with ethyl acetate (3×). The ethyl acetate extract was washed with water, dried and evaporated to give a solid. This was purified by crystallisation from ethyl acetate to give the title compound (1.67 g), m.p. 199°-202°, [α]D +6.5°.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
Methyl 4-hydroxy-2-methyl-5-nitrobenzoate (12.9 g) was dissolved in dimethylformamide (200 ml), and thereto were added potassium carbonate (20.1 g) and benzyl bromide (13.7 g), and the mixture was stirred at 70° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The obtained organic layer was washed with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The obtained solid was washed with hexane/ethyl acetate=10/1 to give the title compound (13 g).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([O:10][CH:11]2[O:16][CH:15]([CH2:17][OH:18])[CH:14]([OH:19])[CH:13]([OH:20])[CH:12]2[OH:21])[CH:2]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C@@H:11]1([O:10][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]1[OH:21]
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 80 %

Procedure:
p-nitrophenyl-β-D-glucopyranoside (Tokyo Chemical Industries) (250 mg) was dissolved in a methanol/tetrahydrofuran mixed solvent (20 ml/5 ml), and 10% palladium carbon (250 mg) was added to this solution. Hydrogen gas was introduced under a nitrogen gas atmosphere into the reaction solution at room temperature for 3 hours. The reaction mixture was filtered to remove palladium carbon, the filtrate was evaporated under vacuum, and solidified. This residue was purified by silica gel chromatography using a tetrahydrofuran/chloroform mixed solvent (1/1, volume ratio) as an eluant, and p-aminophenol-β-D-glucopyranoside was obtained.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([Cl:15])[N:11]([CH2:16][CH:17]=[CH2:18])[C:10]=2[C:9](=[O:19])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28]O)[CH:23]=[N:22]1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:15][C:12]1[N:11]([CH2:16][CH:17]=[CH2:18])[C:10]2[C:9](=[O:19])[N:8]([CH2:28][CH2:27][CH2:26][C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[C:7](=[O:20])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCc1cn[nH]c1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Reaction time: 18 h
Yield: 42.5 %

Procedure:
3-Pentyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5 g, 16.86 mmol) and 3-(1H-pyrazol-4-yl)propan-1-ol (2.12 g, 16.8 mmol) were stirred in dry THF (150 ml) at 3° C. Dibenzyl azodicarboxylate (10.05 g, 33.7 mmol) was added followed by the dropwise addition of triphenylphosphine (8.83 g, 33.7 mmol) in dry THF (70 ml). The mixture was allowed to warm to it and stirred for 18 h. Water (1 ml) was added and the solvents evaporated. The residue was taken up in Et2O (200 ml) from which a white solid, mostly triphenylphosphine oxide, crystallised and was filtered off. The filtrate was concentrated and further by-products crystallised from ether-cyclohexane. The remaining filtrate was concentrated (19.2 g) and purified on a Biotage™ system (400 g) eluting with EtOAc-cyclohexane (2:1) to afford the title compound as a white solid (2.89 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1O)=[O:19].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:16][O:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:19]
Reactant: COC(=O)c1c(O)cnc2ccc(OC)cc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)cnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Trifluoromethanesulfonic anhydride (3.35 mL, 19.94 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-hydroxy-6-methoxy-quinoline-4-carboxylic acid methyl ester (3.1 g, 13.29 mmol, 1.0 eq) in dichloromethane (30 mL), followed by triethylamine (5.6 mL, 39.88 mmol, 3.0 eq). After 1 hour stirring at room temperature, solvent is removed and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylic acid methyl ester as a yellow solid (3.69 g, 76% yield).
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[ClH:12].Cl.[O:14]([CH2:16][CH:17]([F:21])[CH2:18][NH:19][CH3:20])[NH2:15]>C(O)C>[ClH:12].[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[N:15][O:14][CH2:16][CH:17]([F:21])[CH2:18][NH:19][CH3:20]
Reactant: O=Cc1ccccc1O
Reactant: CNCC(F)CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml of 1N sodium hydroxide solution and 305 mg (2.5 mmol) of salicylaldehyde are added to a solution of 488 mg (2.5 mmol) of N-(3-aminoxy-2-fluoropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation and the residue is crystallised from ethanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)(CO)[CH2:5][CH2:4]1.C(N(S(F)(F)[F:33])CC)C.[C:36](=[O:39])([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:4][CH2:5][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)([O:39][CH2:36][F:33])[CH2:7][CH2:8]1
Reactant: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(OCF)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one dimethyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 mL) was added dropwise to a solution of diethylaminosulfur trifluoride (0.14 mL, 1.02 mmol) at -78° C. under an argon atmosphere. The mixture was allowed to warm to room temperature and after 0.75 h, 5aqueous sodium carbonate was added. The mixture was extracted with chloroform, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide a yellow oil (0.3 g, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][C@H:29]([CH2:40][OH:41])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:24]([NH:28][C@H:29]([CH2:40][OH:41])[CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:39])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 140 mg (0.38 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine and 120 mg (0.50 mmol) of tert-butyl [(3S)-3-amino-4-hydroxybutyl]carbamate hydrochloride (Example 88A) in 6 ml of dimethylformamide with the addition of 96 mg (0.50 mmol) of EDC, 16 mg (0.12 mmol) of HOBt and 0.17 ml (1.00 mmol) of diisopropylethylamine. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→10:90).
Reaction SMILES: Br[C@@H]1C[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1O.[C:12](#[N:14])[CH3:13].[OH2:15]>S(=O)(=O)(O)O>[NH2:14][C@@H:12]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:13]1[OH:15]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Reactant: CC#N
Reactant: O
Agent: O=S(=O)(O)O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Into a 10 ml eggplant-type flask, 1.07 g (5.0 mmol) of trans-(+)-2-bromo-1-indanol (I: X=OH, Y=Br; optical purity: 81.6% e.e.) and 2.6 ml of acetonitrile were introduced. While this mixture was stirred with a magnetic stirrer and cooled in a water bath, 0.76 g (7.5 mmol) of 97% sulfuric acid was dropwise added thereto in a period of 2 hours. The resulting mixture was stirred at room temperature for 1 hour and then 6.5 ml of water was added thereto. After an acetonitrile/water azeotrope was distilled off under a reduced pressure of 200 mmHg at a bath temperature of 40° C., the remaining mixture was heated to 80° C. under normal pressure and then stirred at the same temperature for 4.5 hours. This reaction liquid was cooled to room temperature and then washed twice with 10 ml of dichloromethane. After a liquid separation, the pH of the water phase was adjusted to 11 by an addition of an aqueous solution of 25% sodium hydroxide. This phase was extracted with 10 ml of dichloromethane three times and then dried with sodium sulfate anhydride. After the solvent was distilled off from the remaining liquid, 0.60 g of a crude product was obtained. This product was dissolved in 97% sulfuric acid and then washed twice with 10 ml of dichloromethane. Thereafter, while this solution was cooled to room temperature, 25% sodium hydroxide was added thereto to attain a pH of 7. Then, the solution was washed twice with 10 ml of dichloromethane. By an addition of 25% sodium hydroxide, the pH of the solution was adjusted to 11. Thereafter, this solution was extracted with dichloromethane, dried with sodium sulfate anhydride, and then evaporated to dryness in vacuo to yield 0.38 g of cis-(-)-1-aminoindan-2-ol (V) as a white crystal (yield: 51.0%). According to an HPLC, its chemical purity and optical purity were 98.5% and 82.0% e.e., respectively.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:46]1([NH:51][C:52]2[CH:57]=[CH:56][C:55]([S:58]([O:61][C:62]3[CH:71]=[CH:70][C:65]4[NH:66][C:67]([NH2:69])=[N:68][C:64]=4[CH:63]=3)(=[O:60])=[O:59])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[CH:46]1([NH:51][C:52]2[CH:57]=[CH:56][C:55]([S:58]([O:61][C:62]3[CH:71]=[CH:70][C:65]4[NH:66][C:67]([NH:69][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:68][C:64]=4[CH:63]=3)(=[O:59])=[O:60])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.3 mg of N-(tert-butoxycarbonyl)glycine, 25 mg HBTU and 12 μl diisopropylethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 2.4 mg of N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-tert-butoxycarbonylglycineamid. (LC/MS analysis: retention time=3.87 min., mass spectrum: 530.38, [M+H]+).