Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](I)[CH3:30]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:29][CH3:30])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Product: CCOc1cc(CC)cc(OCCCCCC(C)(C)C#N)c1OCc1ccccc1
Yield: 38 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl -6-ethoxy benzene was prepared in 38% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and ethyliodide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=O.[C:23]([CH2:26][C:27](=O)[CH3:28])(=[O:25])[CH3:24]>CCCCCCC.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:27]([CH3:28])[C:26]=2[C:23](=[O:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1ccc(Cl)c(Cl)c1
Yield: 59 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3,4-dichloro-phenyl)-methanone [example A4] and acetylacetone according to the method of example 1, except that heptane/ethyl acetate (1:2). Yield: 59%. MS: m/z=414 (M).
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13](Cl)=[C:14]([Cl:17])[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([Cl:17])[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Cl)c(Cl)c(Sc2ccccc2)c(Cl)c1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2 g (5.86 millimols) of tetrachlorophthalic acid N-n-butylimide are initially introduced, together with 2.43 g (17.59 millimols) of potassium carbonate, into 15 ml of tetrahydrofuran at 0° C. A solution of 680 mg (6.16 millimols) of thiophenol in 10 ml of tetrahydrofuran is added dropwise over a period of 2 hours. The mixture is stirred at 0° C. for 3 hours and gradually warmed to 25° C. over a period of 6 hours, and then acidified with 2N HCl solution and extracted with tetrahydrofuran/toluene. After drying over sodium sulfate, the organic phase is evaporated and the residue is recrystallised several times. This yields 0.17 g (7% of theory) of 4-phenylthio-3,5,6-trichlorophthalic acid N-n-butylimide; melting point 159°-63° C.
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>>[CH2:1]([N:4]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:5]1)[CH2:2][CH3:3]
Reactant: CCCNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Product: CCCn1ncc2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from propylhydrazine and 2-(dimethylaminomethylene)-cyclohexane- 1,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:48](O)=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C@H:37]([C:48]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3 (1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-tryptophan N-hydroxysuccimmlde ester (547 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (71% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[OH-].[Na+].O.S(OC)(O[CH3:20])(=O)=O>CCOCC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:20])=[C:6]([Cl:11])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)c(Cl)c1

Procedure:
To a cooled solution of 14.5 g. (0.078 mol.) of 3-chloro-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) of sodium hydroxide in 100 ml. of water was dropwise added 9.8 g. (7.3 ml., 0.079 mol.) of dimethyl sulfate. The reaction mixture was refluxed for two hours. After cooling, ether was added and the layers were separated. The organic phase was washed with water, dilute sulfuric acid and water, dried (Na2SO4) and concentrated in vacuo to give 3-chloro-4-methoxybenzoic acid methyl ester, m.p. 72°-74°.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([CH2:24][C:25](O)=[O:26])#[N:23]>>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:25](=[O:26])[CH2:24][C:22]#[N:23])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Reactant: N#CCC(=O)O
Product: N#CCC(=O)Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Yield: 47.1 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(phenylthio)pyrimidin-2-yl)benzene-1,3-diamine (80 mg, 0.27 mmol) and cyanoacetic acid (46 mg, 0.54 mmol) furnished the product (46 mg, 47%).
Reaction SMILES: [C:1]([O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:11]=1[O:23][CH3:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[C:1]([O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[O:19][C:20]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[CH:21][CH:22]=2)=[CH:12][C:11]=1[O:23][CH3:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC(=O)c1ccccc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
4-(Furan-2-yl)-2,6-dimethoxyphenyl benzoate was reacted with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure described for the synthesis of Example 12 except that the reaction was warmed to only 0° C. Purification by chromatography (EtOAc-hexanes) provided 2,6-dimethoxy-4-(5-(2-methoxy-2-(4-morpholinophenyl)acetyl)furan-2-yl)phenyl benzoate as a yellow solid (0.257 g, 50% yield). MS: m/z 558.2 [M+H]+.
Reaction SMILES: N[C:2]1[C:13]([C:14]([O:16]N2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1)([O-:28])=[O:27].O1CC(=O)C1.CO>C1COCC1>[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:35]1[CH2:36][CH2:37][N:38]([CH:13]2[CH2:14][O:16][CH2:2]2)[CH2:39][CH:40]=1)([O-:28])=[O:27]
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Reactant: O=[N+]([O-])c1cnccc1C1=CCNCC1
Agent: O=C1COC1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnccc1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
Sodium triacetoxyborohydride (Sodium Ion (1)) (1.189 g, 5.608 mmol) was added in portions to a stirred solution of 3-nitro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (523 mg, 2.549 mmol) and 3-oxetanone (312.2 mg, 277.8 μL, 4.333 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to warm to ambient temperature and was stirred for 16 hours. MeOH (2 mL) was added dropwise and the mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was partitioned between water and EtAOc. The pH of the aqueous layer was adjusted to pH 7-8 by the addition of NH4OH and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo to give 3′-nitro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as a red oil (615 mg, 92% Yield). MS (ES+) 262.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1C=CC([I+][C:16]2[C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1>CO.[OH-].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Reactant: Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Oc1ccccc1C(=O)O
Temperature: 90 °C
Reaction time: 10 h
Yield: 64.6 %

Procedure:
A solution of 2-methylphenol (III: R3 =H) (33 g, 305 mmol) in MeOH (100 mL) was treated with Na (2.1 g, 90 mmol), and excess MeOH was removed under reduced pressure. Diphenyliodonium-2-carboxylate (II: R1 =H) (19.6 g, 60 mmol) and cupric acetate (0.5 g) were added and the mixture was stirred at 90° C. for 10 h. The solution was diluted with 2N NaOH, filtered through celite and acidified with HCl. The mixture was then dissolved in 2N K2CO3 and extracted twice with EtOAc to remove excess 2-methylphenol. The aqueous layer was then poured into excess 2N HCl to give 2-(2-methylphenoxy)benzoic acid (IV: R1 =R3 =H) (8.85 g, 64%), suitable for the next step. A sample crystallized from ligroin, mp 133°-134° C. (Ber, 1905, 38, 2111 records mp 133.5° C.).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:44])[NH:35][O:36][Si](C(C)(C)C)(C)C)[CH:29]=1)(=[O:3])[CH3:2].[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:44])[NH:35][OH:36])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)NO[Si](C)(C)C(C)(C)C)nn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)NO)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-[(1-{4-[N-(t-butyldimethylsilyloxy)carbamoyl]butyl}-1H-1,2,3-triazol-4-yl)methylidene]-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (148 mg) in dichloromethane (3 ml) was added 4N solution of hydrogen chloride in dioxane (230 μl) at 0° C. The resulting mixture was stirred at room temperature for 15 minutes. The solvent and excess hydrogen chloride were removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of methanol and dichloromethane (3:97 to 15:85) as the eluent to afford (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[4-(N-hydroxycarbamoyl)butyl]-1H-1,2,3-triazol-4-yl}methylidene)piperidine hydrochloride (110 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=1[CH2:17][NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:21][CH2:20]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=1[CH2:17][NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)Nc1c(Br)cc(Br)cc1CN[C@H]1CC[C@H](OC(=O)CCCO[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc(Br)cc1CN[C@H]1CC[C@H](OC(=O)CCCO[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(nitroxy)butyric acid 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]trans cyclohexyl ester (3.5 g, 5.74 mmoles) in ethyl acetate (100 ml), cooled at 0° C., a 5N HCl solution in ethyl acetate (5.95 ml) is added. The solution is maintained under stirring at 0° C. for 5 hours, then filtered. The obtained solid is suspended in ethyl acetate and the organic layer washed with a 5% sodium carbonate solution. The organic phase is washed with water, anhydrified with sodium sulphate and evaporated at reduced pressure. The residue is purified by chromatography on silica gel, eluting with n-hexane/ethyl acetate 1/1 (ratio by volume). 4-(nitroxy)butyric acid 4-[(2-amino-3,5-dibromophenyl) methylamino]trans cyclohexyl ester is obtained. Yield 31%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:29][C:26]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][CH2:17][C:16]([NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (2.29 g, 5.16 mmol) in CH3OH (40 mL) was treated with 1 N HCl-Et2O (55 mL). The reaction mixture was stirred at 25° C. for 15 h and the solvent was removed under reduced pressure. 2 N aqueous NaOH solution (100 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine and dried (K2CO3). The solvent was removed under reduced pressure to afford a white solid which was purified by column chromatography (SiO2, CH3OH/CH2Cl2/Et3N=7/6/1)) to give 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (1.27 g, 72%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 344.1 (M++H, C16H20F3N3O2).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:21]([CH3:23])=[CH2:22])[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:19])=[CH:15][CH:16]([OH:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].CCCCCC.C(OCC)(=O)C>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([Si:5]([CH3:24])([CH3:25])[O:6][CH:7]([C:21]([CH3:23])=[CH2:22])[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:19])=[CH:15][C:16](=[O:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC(C)O)O[Si](C)(C)C(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(C)C(CC/C(C)=C/CCC(C)=CC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 g of (7E)-11-(tert.-butyldimethylsiloxy)-4,8,12-trimethyl-3,7,12-tridecatrien-2-ol are added dropwise at 0° to a suspension of 25 g of manganese dioxide (active, precipitated) in 50 ml of dichloromethane. After stirring at room temperature for 5 hours the reaction mixture is filtered over sodium sulphate and the filtrate is evaporated. The material obtained is subjected twice more to the same oxidation process with fresh manganese dioxide each time in order to achieve complete reaction. Chromatography of the crude product obtained on silica gel with hexane-ethyl acetate 2%→5% yields (7E)-11-(tert.-butyldimethylsiloxy)-4,8,12-trimethyl-3,7,12-tridecatrien-2-one as a yellowish which has a purity of 95% in accordance with a gas chromatography. NMR (250 MHz, CDCl3): 6.05 (s, H-C(3)); 5.1 (m, H-C(7)); 4.84 and 4.75 (2m, 2H-C(13)); 4.0 (t, J=6.5, H-C(11)); 2.3-1.4 (m, 4CH2, 3CH 3); 0.89 (s, SiC(CH3)3); 0.35 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(N)c1N
Yield: 100.2 %

Procedure:
A solution of methyl 2-amino-4-methoxy-3-nitrobenzoate (1.84 g, Reference Example 9) in ethanol (100 ml) was treated with 10% palladium on carbon (0.2 g). The resulting suspension was stirred under 3 atmospheres of hydrogen for 3 hours. The catalyst was then removed by filtration and the filtrate evaporated to give the title compound 1.6 g) as a black solid which was used without further purification. M+196.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]([OH:7])=O)([CH3:3])[CH3:2]>C(Cl)(=O)C>[CH:1]([CH:4]1[CH2:8][CH2:9][C:10](=[O:11])[O:12][C:5]1=[O:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(CCC(=O)O)C(=O)O
Solvent: CC(=O)Cl
Product: CC(C)C1CCC(=O)OC1=O

Procedure:
The starting material is prepared as follows: A solution of 14.0 g of 2-isopropylglutaric acid in 80 ml of acetyl chloride is stirred at 50° for 2 hours and then evaporated to give 2-isopropylglutaric anhydride with NMR peaks at 0.98, 1.89, 2.43 and 2.85 ppm.
Reaction SMILES: C(N[C@H](C(O)=O)CCCNC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34][C:35](=[O:67])[C@@H:36]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[NH:37][C:38](=[O:59])[C@H:39]([CH2:48][CH2:49][CH2:50][NH:51]C(OC(C)(C)C)=O)[NH:40]C(OC(C)(C)C)=O.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34][C:35](=[O:67])[C@@H:36]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[NH:37][C:38](=[O:59])[C@@H:39]([CH2:48][CH2:49][CH2:50][NH2:51])[NH2:40]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccccc1)C(=O)Sc1ccc2ccccc2c1
Agent: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@@H](N)C(=O)N[C@H](Cc1ccccc1)C(=O)Sc1ccc2ccccc2c1

Procedure:
N-Boc-D-phenylalaninyl 2-naphthyl thioether was deprotected (Procedure E) to afford D-phenylalaninyl 2-naphthyl thioether trifluoroacetate which was coupled (Procedure B) with Nα,Nδ-bis-Boc-ornithine. The Nα,Nδ-bis-Boc-ornithyl-D-phenylalaninyl 2-naphthyl thioether was deprotected by exposure to trifluoroacetic acid to afford after HPLC purification the titled compound: 1H NMR (400 MHz, D2O) δ1.60-1.70 (4H), 2.64-2.70 (2H), 2.90-3.30 (3H), 3.41-3.50 (1H), 3.80-3.82 (1H), 4.39-4.41 (1H), 7.23-7.70 (8H), and 7.80-8.05 (4H); mass spectrum (relative intensity) m/e 408 (100, M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])[CH:11](N2C(SSC3SC4C=CC=CC=4N=3)C(NC(=O)COC3C=CC=CC=3)C2=O)[C:12](=[CH2:14])[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]>CC(C)=O.O.C1(C)C=CC(S([O-])=O)=CC=1.[Ag+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:42])[CH2:11][C:12](=[CH2:13])[CH3:14])=[CH:43][CH:44]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Agent: [Ag+]
Agent: Cc1ccc(S(=O)[O-])cc1
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(ci) 1.58 g (1.2 equivalents) of silver p-toluenesulphinate are added in portions, in the course of 10 minutes, to a solution of 3.25 g (5.0 mmols) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester in 200 ml of acetone/water, 9:1 (v/v). The suspension is stirred for one hour at room temperature, filtered and further processed as described in Example 1(c). 2-[4-(p]Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester is obtained in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[C:34]2[CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:42](=[O:43])[CH2:41][C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([O:30][CH3:29])[CH:32]=4)[NH:36][C:35]=3[CH3:40])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)Cc2c(C)[nH]c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (202 mg, 0.50 mmol), in N,N-dimethylformamide (4 ml) was added 5-methoxy-2-methyl-3-indole acetic acid (170 mg, 0.74 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide, hydrochloride (150 mg, 0.75 mmol), and 1-hydroxybenzotriazole (105 mg, 0.74 mmol). The mixture was stirred at room temperature for 12 hours. The crude reaction mixture was diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo, which afforded 2-amino-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([OH:27])=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:5]=[C:6]2[C:10]=1[N:9]([C:25]([C:21]1[O:20][CH:24]=[CH:23][CH:22]=1)=[O:27])[N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1
Reactant: O=C(O)c1ccco1
Product: O=C(Nc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(=O)c1ccco1)c1ccco1
Yield: 37.9 %

Procedure:
Following amidation using 217 mg of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-ylamine and 286 mg of 2-furancarboxylic acid in accordance with the method of Example 127, purification by LC-MS was carried out, to afford 143 mg of the title compound as yellow crystals.