Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21

Procedure:
A process for producing tetrafluorophthalic anhydride, which comprises reacting 3,4,5,6-tetrafluorophthaloyldifluoride and/or 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone with an Inorganic base or an organic acid to obtain tetrafluorophthalic anhydride.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 41.3 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.72 g.), methanol (10.8 ml.) and conc. hydrochloric acid (0.61 g.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.28 g.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10]Br>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Br:10]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Br)c1
Temperature: 0 °C

Procedure:
In a suspension of 61.1 g (1/2 mole) of 4-hydroxy-benzaldehyde in 600 ml of chloroform cooled to 0° C., there is added drop by drop 27 ml of bromine dissolved in chloroform.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:19][CH2:18]2)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1
Reactant: COc1ccc(CNc2nc(C(=O)N3CCC(N4CCCC4)CC3)c(C)cc2-c2cccc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N)nc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of 1.48 g (2.7 mmol) of [6-(4-methoxy-benzylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 6) in 75 ml of CH2Cl2 was added 12.2 ml=18.2 g (160 mmol) of trifluoroacetic acid and the reaction mixture was subsequently heated up to reflux. After two hours, it was poured into crashed ice, the pH was adjusted to 8-9 with sodium carbonate solution and it was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 3:1) to give 1.04 g (90%) of the title compound as light yellow foam. MS: 433.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C>CO.C(OCC)(=O)C.[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[S:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(N)c3)cs2)cc1
Yield: 79.7 %

Procedure:
A solution of 1.5 g of 4-methyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide in 150 ml of methanol and 70 ml of ethyl acetate was hydrogenated at room temperature after the addition of 0.15 g of palladium on active charcoal (10%). The catalyst was filtered off and the filtrate was concentrated. Crystallization from ethyl acetate/hexane (1:1) yielded 1.1 g of N-[4-(3-amino-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][OH:27])[N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@:10]3([CH2:25][CH:24]3[CH:26]=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CO)c1nnc(C)n1-2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(CC1C=O)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-yl)methanol (Compound 210; 75 mg, 0.188 mmol) in DCM (2 mL) at 0° C. was added Dess-Martin periodinane (96 mg, 0.226 mmol). After 1 h at 0° C., extra Dess-Martin periodinane (96 mg, 0.226 mmol) was added, and the reaction was warmed to rt for 2 h. Then the reaction was diluted with diethylether and filtered. The filtrate was concentrated to dryness under vacuum, and the residue was used without purification in the next step. LRMS (M+H)+: 397 m/z.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[S:10](N)([NH2:13])(=[O:12])=[O:11]>O1CCOCC1>[CH3:9][N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: CNC1CCN(C)CC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CN1CCC(N(C)S(N)(=O)=O)CC1

Procedure:
A solution of 1-methyl-4-(methylamino)piperidine (2.6 g) and sulfamide (4.0 g) in 1,4-dioxane (30 ml) was heated at 110° C. for 18 h. The reaction mixture was cooled, the solvent evaporated under reduced pressure and the residue dissolved in water. The aqueous solution was extracted with EtOAc which was washed with a small volume of saturated aqueous brine, dried (MgSO4) and the solvent evaporated under reduced pressure to give the subtitle product as a pale yellow solid. Yield: 1.5 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[N:16]1[NH:17][C:18]([NH2:21])=[CH:19][CH:20]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:17]3[N:16]=[CH:20][CH:19]=[C:18]3[N:21]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccn[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Oc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 150 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (5.8 g, 26.0 mmol) and 2H-pyrazol-3-ylamine (2.1 g, 26.0 mmol) was stirred at 150° C. for 2 h. EtOAc (22 mL) was successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (4.80 g, 75%) as a white solid. MS (ISP) 246.1 [(M+H)+]; mp 306–308° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([OH:26])=O)[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([NH:32][C:33]3[CH:37]=[CH:36][O:35][N:34]=3)=[O:26])[C:14]4=[O:31])[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C4CCC4)CC3)cc2c1=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C4CCC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 1.74 (m, 2H), 1.96 (m, 2H), 2.07 (m, 2H), 2.28 (s, 3H), 2.55 (m, 4H), 2.83 (m, 1H), 3.39 (m, 4H), 7.20 (s, 1H), 7.46 (m, 1H), 7.53 (d, 1H), 7.67 (m, 2H), 7.85 (s, 1H), 7.91 (s, 1H), 7.99 (d, 1H), 8.26 (s, 1H); Mass Spectrum: M+H+ 485.
Reaction SMILES: [C:1]1([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:17](OCC)C>>[C:1]1([CH2:11][C:12](=[O:16])[C:13]([O:15][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)Cc1cccc2ccccc12
Reactant: CCOCC
Product: COC(=O)C(=O)Cc1cccc2ccccc12

Procedure:
Sodium (677 mg, 29.4 mmol) is dissolved in ethanol (48 ml). To the solution are added 1-naphthylacetonitrile (5.07 g, 30.3 mmol), then after 20 min. diethyl oxalate (4.1 ml, 30.3 mmol) at r.t. and the mixture is stirred at r.t. for 2 hrs. and refluxed for 1 hour. After cooling to r.t. acetic acid (2 ml) is added. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated in vacuo to give 3-cyano-3-(1-napththyl)pyruvate. A mixture of 3-cyano-3-(1-naphthyl)pyruvate (6.56 g, 24.6 mmol) and 30% sulfric acid (400 ml) is heated at 100° C. for 2 hrs. After cooling, the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated on vacuo to give 3-(1-naphthyl)pyruvic acid. To a solution of 3-(1-naphthyl)pyruvic acid(1.86 g, 8.7 mmol) in diethyl ether (20 ml) is added diazomethane diethyl ether solution (25 ml). The mixture is concentrated in vacuo and the residue is chromatographed on silica gel with hexane and ethyl acetate (3:2) to give methyl 3-(1-naphthyl)pyruvate.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9](=[CH:11][CH2:12][CH2:13][CH:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH3:10].N1C=CC=CC=1.CCOCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][CH:14]([CH2:13][CH2:12][CH:11]=[C:9]([CH3:8])[CH3:10])[CH2:16][CH2:17][O:18][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)=CCCC(C)CCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)O
Yield: 47.4 %

Procedure:
A solution of 30.0 g succinic anhydride, 46.9 g citronellol, 36.0 g pyridine and 2.2 g 4-dimethylaminopyridine in 300 ml of dichloromethane was refluxed for 22 hours. Then the solution was cooled, ether was added and the organic phase was washed with 2N HCl and water to neutrality, dried and evaporated to dryness. The residue was wipe-film distilled to yield 36.4 g of a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([CH3:34])=[N:22][O:23][C:24]=3[NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](O[N:52]2N=[N:59][C:54]3C=CC=C[C:53]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:53]([CH2:54][NH:59][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:24]1[O:23][N:22]=[C:21]([CH3:34])[C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1)#[N:52]
Reactant: Cc1noc(N[C@@H](CC(C)C)C(=O)O)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc(N[C@@H](CC(C)C)C(=O)NCC#N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 3 h

Procedure:
To N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucine (415 mg, 0.879 mmol), PyBOP (505 mg, 0.97 mmol), aminoacetonitrile hydrochloride (179 mg, 1.93 mmol) in dry DMF (15 mL) under dry nitrogen was added triethylamine (0.44 mL, 3.1 mmol) dropwise and the reaction was stirred for 3 hours. Aqueous sat. NaHCO3 was added and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 6/4) to afford N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucinamide.
Reaction SMILES: FC1C=CC(C2N=CC=CN=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[N:23]=[C:22]([C:24]([OH:26])=O)[C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[CH:20][CH:19]=1.C(OC(N1[C@@H]2CC[C@H]1[C@H](COC1C=CC=CN=1)C2)=O)(C)(C)C.[Br:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][CH:63]2[CH2:68][CH:67]3[NH:69][CH:64]2[CH2:65][CH2:66]3)=[N:59][CH:60]=1>>[Br:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][CH:63]2[CH2:68][CH:67]3[N:69]([C:24]([C:22]4[C:21]([N:27]5[N:31]=[CH:30][CH:29]=[N:28]5)=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=4)=[O:26])[CH:64]2[CH2:65][CH2:66]3)=[N:59][CH:60]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Reactant: Brc1ccc(OCC2CC3CCC2N3)nc1
Agent: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](COc1ccccn1)C2
Agent: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C3CCC2C(COc2ccc(Br)cn2)C3)n1

Procedure:
Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and (1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of Step A. MS (ESI) mass calcd. for C21H21BrN6O2, 468.1; m/z found 469.1, 471.1 [M+H]+. 1H NMR (CDCl3): 8.20 (d, J=2.6 Hz, 0.4H), 8.16 (d, J=2.6 Hz, 0.6H), 8.13 (d, J=8.3 Hz, 0.4H), 8.10 (d, J=8.4 Hz, 0.6H), 7.82-7.77 (m, 2H), 7.64 (dd, J=8.8, 2.6 Hz, 0.4H), 7.60 (dd, J=8.8, 2.6 Hz, 0.6H), 7.33-7.29 (m, 0.4H), 7.22 (d, J=8.4 Hz, 0.6H), 6.69 (d, J=8.8 Hz, 0.4H), 6.50 (d, J=8.8 Hz, 0.6H), 4.84 (dd, J=11.1, 5.2 Hz, 1H), 4.30-4.04 (m, 2H), 3.93-3.85 (m, 1H), 2.62 (s, 1.3H), 2.38-2.17 (m, 2.7H), 2.11-1.95 (m, 1H), 1.94-1.77 (m, 1H), 1.77-1.40 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H](C(N[C@@H](C(NCC(O)=O)=O)CCSC)=O)CC1C=CC(O)=CC=1>>[NH:1]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[C@@H:2]([C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[CH2:7][CH2:6][C:14](=[O:15])[NH2:16]
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C

Procedure:
Using BOC-(D)-Gln-ONP(0.96 g) and H-Gly-Phe-NHNH-COCH3 (0.72 g), the desired compound (0.95 g) is obtained in a similar manner to (III) of Example 45. m.p. 198°-199° C., [α]D23 -0.8° (C=0.50, DMF), Rf1 =0.19.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:36][C:30]2[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[CH:28]=3)[NH:32][CH:31]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]cc(CN[C@H]3CCN(C(=O)c4cc(Cl)cc(Cl)c4)[C@H](Cc4ccccc4)C3)c2c1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 116 mg (0.661 mmol) of 5-methoxyindole-3-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml of toluene and subsequently reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound ##STR95## is obtained (98 mg, 34%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.42, FD-MS: M+ =521, 523. IR: 3460, 1630 cm-1.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(N)C(NC(=O)OC(C)(C)C)C1
Yield: 10.6 %

Procedure:
A mixture of Racemate-ethyl 4-azido-3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (14.0 g, 66 mmol) and 5% palladium on carbon (50% wet, 1.0 g) in ethyl acetate (100 mL) was stirred at room temperature overnight at a hydrogen pressure of ˜1 atm. After the reaction mixture was filtered, the filtrate was concentrated. The resulting oily residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1˜1:1) to thereby give the title compound (2.0 g, 59%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8].CO.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(F)c(Br)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
To methyl 4-[(2-{1-[5-(3-bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.051 mmol, 24.9 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.255 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.255 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (9.0 mg, yield 37%)
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19]([F:22])([F:21])[F:20]>[Cl-].[Zn+2].[Cl-].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[C:19]([F:20])([F:22])[F:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCC1
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Product: COC(=O)c1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To zinc(II) chloride (0.5 M solution in tetrahydrofuran, 88.0 mL, 44.0 mmol) was added cyclopentylmagnesium chloride (2 M solution in ether, 20.5 mL, 41.1 mmol). The resulting suspension was stirred at room temperature for 1 h. To the above suspension was added methyl 4-chloro-3-(trifluoromethyl)benzoate (7.00 g, 29.3 mmol) and bis(tri-tert-butylphosphine)palladium (1.35 g, 2.64 mmol) at room temperature. The mixture was heated under reflux for 2 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as an oil (7.64 g). LCMS m/z=273.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.57-1.66 (m, 2H), 1.68-1.82 (m, 2H), 1.82-1.94 (m, 2H), 2.04-2.21 (m, 2H), 3.33-3.49 (m, 1H), 3.93 (s, 3H), 7.54 (d, J=8.21 Hz, 1H), 8.13 (dd, J=8.34, 1.77 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.CC(C)=[O:28]>O>[OH:28][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: CC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(O)cc2C1
Yield: 92 %

Procedure:
To a stirred solution of (R)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (6.21 mmol, 2.27 g) in acetone (20.00 mL), a solution of oxone monopersulfate compound (6.84 mmol, 4.20 g) in Water (20 mL) was added dropwise over 2 min. The resultant solution was stirred for a further 10 min before being quenched with NaHSO3 (aq). The solution was extracted with DCM (×3), dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a colourless oil which solidified to a white solid on standing. The solid was triturated with heptane to give the title compound as a white solid (1.46 g, 92%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N(C(=O)CCCOCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of N-(1-benzylpiperdin-4-yl)-N-isopropyl 4-(2-hydroxyethoxy)butyramide (2.7 g, 7.5 mmol) in THF (20 mL) was slowly added 1 M lithium aluminum hydride in THF (11.3 mL, 11.3 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then quenched by slow addition of 15% aqueous sodium hydroxide at 0° C. until no gas formation was observed. After stirring for 10 minutes at room temperature, a solid formed and the reaction mixture was filtered and the precipatate washed with THF three times. The filtrate was then concentrated and the residue was dissolved in dichloromethane and this solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.13 g of the title intermediate (82% yield).