Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(C(C)=O)cc1)OCC
Temperature: 120 °C
Reaction time: 8 h
Yield: 133.4 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)ethanone (1.00 g, 7.34 mmol) in N,N′-dimethylformamide (24 mL), sodium hydride (purity 50%) (380 mg, 8.07 mmol), and bromoacetaldehyde diethyl acetal (1.30 mL, 8.81 mmol) were added under ice-cold conditions and stirred at 120° C. overnight. Under ice-cold conditions, the reaction solution was added water, and extracted with diethylether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (2.47 g (yield >100%)) was obtained as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)/C=C/c1ccc(F)cc1F
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c(F)c1

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)Cl)c1
Reaction time: 16 h

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]=[C:19]([Cl:21])[N:18]=[C:17](Cl)[C:13]=3[NH:14][C:15]=2[CH:16]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:3][CH2:2][CH2:1][OH:4])[C:13]=3[NH:14][C:15]=2[CH:16]=1
Reactant: Clc1nc(Cl)c2[nH]c3cc(Br)ccc3c2n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
397 mg (6.4 mmol) ethylene glycol was added to 115 mg (4.8 mmol) NaH in 20 ml THF and the mixture was stirred at room temperature for 30 min. Then, 500 mg (1.6 mmol) 7-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole (Example 4) was added and the mixture was refluxed for 5 h. Thereafter, the solvent was removed and the residue was taken up in acetic ester and washed with saturated NaCl solution, dried over Na2SO4 and filtrated. Having removed the solvent, 450 mg (88%) 2-(7-bromo-2-chloro-5H-pyrimido[5,4-b]indol-4-yloxy)ethanol was obtained. ESI-MS [m/z]: 342, 344 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[CH:18]([NH2:22])([CH2:20][CH3:21])C.[CH:23]1C=CC=C[CH:24]=1>>[N:22]1([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:18][CH2:20][CH2:21][CH2:24][CH2:23]1
Reactant: CCC(C)N
Reactant: c1ccccc1
Reactant: COc1ccc(C(=O)CCl)c2c1NC(=O)CC2
Product: O=C(CN1CCCCC1)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 6 h

Procedure:
10 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) was suspended in 50 ml of benzene, and 10 ml of piperidine (III) was added to the suspension followed by allowing the mixture to react while heating under refluxing and stirring for 6 hours. The reaction mixture was filtered to recover the reaction product which was then washed with benzene and then with 50 ml of isopropanol. The resulting insoluble material was dissolved in 150 ml of a 2% aqueous hydrochloric acid. The solution was concentrated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol to obtain 7.5 g of white amorphous 5-piperidinoacetyl-8-hydroxycarbostyril (IIb) hydrochloride 1/2 hydrate having a melting point of 239° to 241°C (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3([C:14]([F:17])([F:16])[F:15])[O:13][CH2:12][CH2:11][O:10]3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[CH3:32]N(C=O)C>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:7]([C:9]3([C:14]([F:16])([F:15])[F:17])[O:10][CH2:11][CH:32]=[CH:12][O:13]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccn1
Reactant: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)OCCO1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3n2Cc2ccccn2)OC=CCO1
Reaction time: 0.33 h

Procedure:
5,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole (0.37 g; 1.1 mmol) was dissolved in DMF (6 mL), treated with 60% NaH in mineral oil 9.14 g; 3.5 mmol) and stirred under a nitrogen atmosphere for 20 minutes. Subsequently, 2-(Bromomethyl)pyridine hydrobromide (0.44 g; 1.7 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 mL) and diethyl ether (25 mL), washed with water (30 mL) and brine (3×30 mL), then dried over Na2SO4. The concentrated crude material was purified by column chromatography (SiO2; 50% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.N1C=CN=C1N[C:22](C1C2NC(N)=NC=2C=CC=1)=[O:23].[CH3:34]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:15][C:13]([C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[CH:12][C:11]=2[O:23][CH3:22])=[O:14]
Reactant: COc1ccc2cnc(C(=O)O)cc2c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(OC)c2cn1
Yield: 97.8 %

Procedure:
224 mg (1.1 mmol) of 6-methoxy-isoquinoline-3-carboxylic acid was reacted with 242 mg (1 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 569 mg (1.5 mmol) of HBTU, 0.704 ml (4 mmol) of DIEA and 5 mL of DMF stirring at 80° C. for 2 h as describe in general procedure A to provide 212.4 mg (50%) of the title compound. 1H-NMR (400 MHz, DMSO): 9.37 (s, 1H), 8.71 (s, 1H), 8.24 (d, 1H), 7.94 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.49 (dd, 1H), 7.34 (t, 1H), 6.88 (s, 1H), 6.76 (s, 1H), 3.98 (s, 3H) ppm; LCMS: 428 (M+1)+.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=C)=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.S([O-])([O-])=[O:35].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][OH:35])=[CH:28][CH:29]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Reactant: O=S([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(CO)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 69 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 56 in 2 ml of tetrahydrofuran-water (1:1), 85 mg of sodium periodide and 0.1 ml of 2% osmium tetraoxide were added at 0° C., followed by an hour's stirring at the same temperature. Adding sodium sulfite to the reaction liquid, stirring was continued for further 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was dissolved in 1 ml of methanol. To the solution 10 mg of sodium borohydride was added, stirred for 10 minutes and acetone was added. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on preparative thin layer chromatography (Kieselgel™60F254, Art 5744 (Merck), hexane/ethyl acetate=1/1) to provide 42 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:52]1([CH2:55]Br)[CH2:54][CH2:53]1.O>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([CH2:55][CH:52]2[CH2:54][CH2:53]2)[CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:19])=[O:20])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCNC[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(CC4CC4)C[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(R)-carboxamide (424 mg, 0.68 mmol) [prepared by proceeding as described in Example 15, Steps 4 and 5, but substituting 4-(4,5,6,7-tetra-fluoroindol-3-yl)piperidinesulfamoyl chloride with 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidinesulfamoyl chloride] in DMF (3 ml) was added potassium carbonate (470 mg, 3.4 mmol) and cyclopropylmethyl bromide (101 mg, 0.75 mmol) and the suspension was vigorously stirred at RT for 24 h. Water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, PTLC, 50% ethyl acetate/hexanes) to give N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}-4-cyclopropylmethylpiperazine-2-(R)-carboxamide as a pale yellow oil. This material was converted to N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-cyclopropylmethylpiperazine-2-(R)-carboxamide by proceeding as described in Example 20, Step 2.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].CC(C)=O>>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1CSc2cc(O)ccc2N1
Solvent: CC(C)=O
Product: O=C1CSc2cc(OCCCCl)ccc2N1
Reaction time: 24 h
Yield: 50.4 %

Procedure:
After a mixture consisting of 7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one (1.812 g, 10 mmol), 1bromo-3-chloropropane (2.362 g, 15 mmol), potassium carbate (4.146 g, 30 mmol) and acetone (40 mmol) was heated under reflux and stirring for 24 hours, insolube matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel column (developer: chloroform) to purify the same, and was then recrystallized from acetone. The title compound (1.300 g) was obtained as yellow leaflets (yield: 50.4%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:37]([C@H:40]1[CH2:44][O:43][C:42](=[O:45])[NH:41]1)([CH3:39])[CH3:38].C([Li])CCC.C([O-])(=O)C(C)(C)C>O1CCCC1>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([N:41]2[C@@H:40]([CH:37]([CH3:39])[CH3:38])[CH2:44][O:43][C:42]2=[O:45])=[O:9])=[CH:5][CH:6]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)[O-]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 1A, 1.12 g, 3.80 mmol) in dry tetrahydrofuran (36 mL) under nitrogen was cooled to −78° C. and then treated with triethylamine (606 mL, 4.35 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with trimethylacetyl chloride (491 mL, 3.98 mmol). The resulting reaction mixture was stirred at −78° C. for 15 min, at which time, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. At this time, the reaction mixture was cooled back to −78° C. for the addition of the chiral auxiliary. Into a separate reaction flask, a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (467.9 mg, 3.62 mmol) in dry tetrahydrofuran (18 mL) under nitrogen was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.80 mmol). After complete addition of the n-butyllithium, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. This cloudy white solution was then added dropwise by syringe to the previously cooled (−78° C.) pivalate solution. The resulting reaction mixture was stirred at −78° C. for 1 h and then allowed to gradually warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was quenched with a saturated aqueous sodium bisulfite solution and concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3 hexanes/ethyl acetate gradient elution) afforded the higher Rf product 3-{2(S)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (679.2 mg, 92%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2310; and the lower Rf product 3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (127.4 mg, 17%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2313.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].Cl.[NH2:17][CH2:18][C:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:18][C:19]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1(O)CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(NCC2(O)CCCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2), 1-(aminomethyl)cyclopentanol hydrochloride (J. Med. Chem. 1981, 24, 12-16) and triethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)[CH:5]=[CH:6][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)[CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: Nc1cccc(C2=NNC(=O)C3CC23)c1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 40 %

Procedure:
6.0 g (29.8 millimoles) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 33), 3.5 g (44.6 millimoles) of acetyl chloride and 100 ml of anhydrous toluene are kept at 80° C. for 6 hours. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from methanol. 2.9 g (40% of theory) of 2-(m-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 200°-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC#CCO
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC(=O)NCC#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
4-[(tert.-butoxycarbonyl)amino]butanoic acid (5.20 g, 25.6 mmol, prepared in analogy to Houssin et al., (1988) Synthesis 3, 259-261) was dissolved in anhydrous tetrahydrofuran (20 mL), carbonyldimidazole (CDI) (4.56 g, 28.1 mmol) was added and the resulting clear solution was stirred at room temperature for 2 h. Then, the primary amine 11 (3.11 g 25.6 mmol) and trietylamine (7.10 mL, 50.9 mmol) were added and stirring was continued at room temperature for 2 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 40 g, chloroform/ethylacetate 1:1) to give compound 12 (3.59 g, 52%) as a light yellow oil (Rf 0.3, chloroform/ethyl acetate 1:1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:3]=12.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1>O1CCCC1>[CH3:28][N:24]1[C:4]2=[N:5][CH:6]=[C:7]([C:8](=[O:9])[NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=3)=[O:12])[C:2]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:3]2[C:26]([CH3:27])=[N:25]1
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)c(Cl)c12
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2c(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)cnc3c2c(C)nn3C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide (40 mg) was dissolved in tetrahydrofuran (5.0 mL), ethyl piperidine-4-carboxylate (160 mg) was added, and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, the residue was suspended in water (10 mL), the resulting solid was filtered, washed with water, and dried under high vacuum to give ethyl 1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylate as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCC(O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.52 ml of 4-tert-butylbenzaldehyde (3.1 mmol) and 320 mg of [rac]-2-amino-1-(4-fluoro-phenyl)-ethanol (2.06 mmol) were dissolved in 15 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 117 mg (3.1 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with diethylether/heptane, filtered and the solid dried under high vacuo, leading to 410 mg of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine as a white solid (66%). MS (ISP) 302.2 (M+H)+.