Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](CC(O)=O)=[CH:3][CH:2]=1.CN1CC[O:15][CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:32][C:33]([F:59])([F:58])[C:34]1[CH:35]=[C:36]([CH:51]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1)[CH2:37][O:38][C@H:39]1[O:44][CH2:43][CH2:42][NH:41][C@@H:40]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[F:59][C:33]([F:32])([F:58])[C:34]1[CH:35]=[C:36]([CH:51]=[C:52]([C:54]([F:55])([F:56])[F:57])[CH:53]=1)[CH2:37][O:38][C@H:39]1[O:44][CH2:43][CH2:42][N:41]([C:14]([CH2:13][C:5]2[CH:6]=[N:1][CH:2]=[CH:3][CH:4]=2)=[O:15])[C@@H:40]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CN1CCOCC1
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1cccnc1)N1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 55 mg (0.315 mmol) of 4-pyridylacetic acid in 1 mL of CH2Cl2, containing 0.079 mL (0.715 mmol) of N-methylmorpholine, 53 mg (0.37 mmol) of HOBt and 73 mg (0.37 mmol) of EDC was stirred for 10 min. A solution of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from Example 33) in 1 mL of CH2Cl2 was added. After stirring the mixture for 2 h, it was partitioned between water and CH2Cl2. The organic layer was washed with water, brine and dried by filtering through Na2SO4. The filtrate was concentrated and the residue was purified by flash chromatography using 70% EtOAc/hexane to furnish 152 mg (100% yield) of the product.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:52]([F:56])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: FC1(F)CNC1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoroazetidine hydrochloride and isolated as light-yellow gum (11.9 mg, 64%). MS (m/e): 393.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].CN(C)CCO.Cl>O>[Cl:9][C:4]1[CH:3]=[C:2]([NH:10][CH:11]([CH3:12])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: C[C@H](N)C(=O)O
Reactant: Clc1ccc(Br)cc1Cl
Agent: CN(C)CCO
Agent: Cl
Solvent: O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 1-bromo-3,4-dichlorobenzene (5.10 g, 22.1 mmol), L-alanine (2.96 g, 33.2 mmol) copper(I) iodide (421 mg, 2.21 mmol), tri-potassium phosphate n-hydrate (15.3 g, 66.4 mmol), 2-(dimethylamino)ethanol (5.92 g, 66.4 mmol), and water (22 mL) was heated at 90° C. for 40 h, then poured onto ice water. The pH was set to 6 with 25% aq. HCl solution, and the mixture was extracted with EtOAc. The aqueous phase was acidified to pH 4.5 and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc) afforded the title compound (2.71 g, 53%) as a 60:40 mixture of the (S) and (R) stereoisomers. Light brown solid, MS: 232.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:7](=[O:9])[CH3:8])[CH2:3][C:4]([OH:6])=[O:5].[Mn]([O-])(=O)(=O)=[O:12].[K+].S([O-])(O)=O.[Na+].[OH-:22].[Na+]>>[CH3:1][C:2]([CH3:10])([CH2:3][C:4]([OH:6])=[O:5])[C:7](=[O:9])[C:8]([OH:12])=[O:22]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: CC(=O)C(C)(C)CC(=O)O
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Product: CC(C)(CC(=O)O)C(=O)C(=O)O

Procedure:
In 70 ml of 0.43M aqueous solution of sodium hydroxide was dissolved 1.57 g of 3,3-dimethyl-4-oxopentanoic acid. To the solution was added under ice-cooling and stirring 20 ml of a 1.15M aqueous solution of potassium permanganate. The mixture was stirred under ice-cooling for 4 hours, to which was added an aqueous solution of sodium hydogen sulfite. Then the resultant precipitates were filtered off. The filtrate was adjusted to pH 1 with 6N-HCl, followed by extraction with ethyl acetate. The extract solution was washed with water and dried, followed by evaporating off the solvent to leave 1.73 g of 3,3-dimethyl-2-oxoglutaric acid as a colorless oily product. This oily product was dissolved in 15 ml of N,N-dimethylformamide. To the solution were added 1.08 ml of dicyclohexylamine and 1.18 g of 4-nitrobenzyl bromide. The mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate and the crystals which separated out were filtered off. The filtrate was washed with water and dried (MgSO4), followed by evaporating off the solvent. The residue was chromatographed on silica gel. Elution with hexane-ethyl acetate (2:1) afforded 1.30 g of the subject Compound(67) as colorless crystals. Recrystallization from ethyl acetate yielded colorless prisms, m.p. 134°-135° C.
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[F:12][C:13]([F:27])([F:26])[C:14]1[NH:15][C:16]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:17]=2[N:18]=1.[N+](C1NC2C=CC=CC=2N=1)([O-])=O>FC(F)(F)C(O)=O.CCOC(C)=O.CO.[Pd]>[F:27][C:13]([F:12])([F:26])[C:14]1[NH:15][C:16]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1ccc2nc(C(F)(F)F)[nH]c2c1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reaction time: 12 h
Yield: 80 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (3.0 g, 20 mmol) in 15 ml of trifluoroacetic acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a oily residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to provide an oil which was characterized as 2-trifluoromethyl-5-nitrobenzimidazole and subjected to the following reaction without further purification. The nitrobenzimidazole and 500 mg of 10% Pd—C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 3.2 g (16 mmol, 80%) of the desired product.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH2:34][CH3:35]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12]O)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][N:29]=[N+:30]=[N-:31])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
To a solution of ((1S)-1-hydroxymethyl-2-methylpropyl)carbamic acid t-butyl ester (3.00 g, 14.8 mmol) (obtained as described in Reference Example 61(1)) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (4.78 ml, 22.2 mmol), triphenylphosphine (5.82 g, 22.2 mmol) and a 40% solution of diethylazodicarboxylate in toluene (9.67 g, 22.2 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred for 2 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (9:1) as the eluant to afford ((1S)-1-azidomethyl-2-methylpropyl)carbamic acid t-butyl ester (3.26 g, yield 90%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:18][C:19](=[O:29])[CH2:20][NH:21]C(=O)OC(C)(C)C)[B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:16])[CH3:15].Cl>C(Cl)Cl.O1CCOCC1>[NH2:21][CH2:20][C:19]([NH:18][C@H:4]([B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:15])[CH3:16])[CH2:3][CH:2]([CH3:30])[CH3:1])=[O:29]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]carbamate (2.5 g, 5.9 mmol) in DCM (15 mL) was added 4M HCl in dioxane (5.9 mL The reaction mixture was allowed to stir for 2 h and concentrated to give 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide which was used in the next step without purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH3:16].C(#N)C>C(OC)(C)(C)C>[Cl-:1].[N:5]1([C:3](=[O:4])[CH2:2][N:13]2[CH:14]=[CH:15][N+:11]([CH3:10])=[C:12]2[CH3:16])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCC1
Reactant: Cc1nccn1C
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1n(CC(=O)N2CCCC2)cc[n+]1C
Product: [Cl-]
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
A mixture of N-(chloroacetyl)pyrrolidine (2.0 g, 13.55 mmol) and 1,2-dimethylimidazole (1.3 g, 13.5 mmol) were heated neat at 110° C. for 3 hours. To the reaction mixture was added acetonitrile (5 mL), and heating was continued for 20 minutes. Tert-butyl methylether (10 mL) was added, and the resulting mixture was allowed to stand at room temperature overnight. The product was recovered by filtration, and washed with a mixture of tert-butyl methyl ether and acetonitrile (7:3 v/v, 50 mL). The crude product was recrystallized from a mixture of acetonitrile and tert-butyl methyl ether to obtain 1.23 g (41%) of a white solid; mp 191-193° C.
Reaction SMILES: [CH2:1]([N:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[CH2:1]([N:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: CCN(Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCN(Cc1ccccc1)c1ccc(Br)cc1
Reaction time: 20 h
Yield: 76.6 %

Procedure:
N-benzyl-N-phenyl-N-ethylamine (2.25 g, 0.0107 mol) was dissolved in anhydrous dichloromethane (80 mL) and 2,4,4,6-tetrabromocyclohexadiene-1-one (4.36 g, 0.0107 mol) was added in 6 equal portions over a 20 min. period. Stirring was continued at ambient temperature for 20 hours; the organic phase was successively washed with 0.5N solution of sodium hydroxide in water (50 mL), 1N solution of sodium hydroxide in water (50 mL), water (70 mL) and brine (75 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:99) as mobile phase to yield N-benzyl-N-(4-bromophenyl)-N-ethylamine (2.38 g, 0.0082 mol) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].[CH2:43]([Zn]CC)[CH3:44].C1(C)C=CC=CC=1.O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH2:43][CH3:44])=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (93.5 mg, 0.149 mmol) was dissolved in dimethoxyethane (4.7 mL), and the solution was added with 1.1 mmol/L diethyl zinc-toluene solution (0.68 mL, 0.744 mmol) and [bis(diphenylphosphino)ferrocene]dichloropalladium (34.4 mg, 0.030 mmol), followed by stirring at 90° C. for 12 hours under argon atmosphere. The reaction mixture was added with water and filtered using Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-ethyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (39.0 mg, yield 52%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>CCOCC>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=S)N(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 54.7 %

Procedure:
A mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.6 g (0.025 mole) triethylamine, 3.2 g (0.025 mole) dimethylthiocarbamoyl chloride, and 100 ml ether was refluxed 16 hours. A trace of dark solid was filtered out and the solution was evaporated on a steam bath to give a solid residue. This residue was extracted with hot ligroin to yield 4.3 g (55% yield) of product (mp 81°-83° C.) on cooling. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.C>CO>[C:13]1([N:19]2[C:5]([OH:7])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
A mixture of 44 ml (0.3 mol) of ethyl trifluoroacetoacetate and 33 mL (335.4 mmol) of phenylhydrazine in 60 ml of methanol containing 6 ml of conc. HCl solution was refluxed with stirring for 1.5 hours. After adding activated charcoal with stirring, the hot mixture was filtered. The residue was washed with methanol (2×70 ml), diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 54.3 g (79%) of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole as a pale solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-{4-(4-Oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218–220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.60 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–3.00 (m, 5 H), 3.00–3.50 (m, 3 H), 3.50–3.70 (m, 2 H), 3.85–4.00 (m, 3 H), 4.48 (dd, J=9.8, 3.8 Hz, 1 H), 6.85 (d, J=8.6 Hz, 2 H), 6.90–6.97 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H), 7.25–7.38 (m, 3 H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S (M+): 455.1878. Found: 455.1880.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH2:13][C:6]1=2>>[OH:4][N:3]([CH3:2])[C:15]([NH:14][CH:10]1[C:7]2[CH:8]=[CH:9][S:5][C:6]=2[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: CNO
Reactant: O=C=NC1CCCc2sccc21
Agent: Cl
Product: CN(O)C(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 6, N-methylhydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to afford 1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystallized from acetone-hexane-ether to give crystals, with melting point 98° C. to 102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([NH:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(O)(C)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(=O)Nc1ccc(OCCNCc2ccccc2)cc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-acetamidophenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 2 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was dissolved in hot isopropanol and the solution cooled, the precipitated solid then being collected by filtration. To a hot solution of the solid in fresh isopropanol were added a few milliliters of ethyl acetate, and the solution was then allowed to cool to room temperature. The crystallized solid was collected by filtration, washed in diethyl ether and dried. Recrystallization from an isopropanol/ethyl acetate mixture afforded N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-acetamidophenoxy)ethylamine (32.8 g.), m.p. 104°-6°C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2F)CCCC1=O
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
40% Methanolic Triton B (2.82 mL, 6.2 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.27 g, 5.22 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-fluorobenzyl bromide (1.19 g, 6.2 mM) was added and the resultant mixture stirred at room temperature for 17 days. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.00 g (55%) of the 9-[(2-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 4H), 7.1 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1652, 1464, 1441, 1288 and 1120. MS (ES) m/e 350, 352.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([C:15]([NH:17][C@H:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[O:12][C:11]2=[O:33])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([C:15]([NH:17][C@H:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]([OH:21])=[O:20])=[O:16])[O:12][C:11]2=[O:33])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3].[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C(=N)N)cc2)C(=O)O1
Reactant: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(N2CC(C(=O)N[C@H](Cc3ccccc3)C(=O)O)OC2=O)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
0.25 g of tert-butyl (2R)-2-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonylamino)-3phenylpropionate [obtainable according to Example 12]is stirred in 10 ml of trifluoroacetic acid at room temperature until hydrolysis is complete. The reaction mixture is subsequently concentrated and the residue is washed repeatedly with toluene. Treatment with ethyl acetate gives (2R)-2-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionic acid, trifluoroacetate, FAB (M+1): 397.