Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH2:9][CH:8]1[CH2:26][CH2:27][OH:28]>ClCCl.N1C=CC=CC=1>[CH3:4][S:1]([O:28][CH2:27][CH2:26][CH:8]1[CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:24])[CH3:25])[CH:14]=2)[CH2:11][CH2:12][N:7]1[CH3:6])(=[O:3])=[O:2]
Reactant: CC(C)Oc1cc(N2CCN(C)C(CCO)C2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(N2CCN(C)C(CCOS(C)(=O)=O)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 microliters of mesyl chloride are added to a solution of 160 mg of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanol in 2 ml of dichloromethane and 0.2 ml of pyridine. The reaction medium is stirred at ambient temperature overnight and then concentrated under vacuum, under reduced pressure, so as to give 190 mg of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethyl methanesulfonate in the form of an orangey-coloured oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:18])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[S:12][CH:13]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:18])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(-c2c(C3CC3)cnn2C)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(C2CC2)c1-c1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.42 g, 1.60 mmol) in Tetrahydrofuran (THF) (8 ml). 6N NaOH (8 ml, 48.0 mmol) was added slowly and the reaction stirred at 70° C. overnight. The reaction was cooled and partitioned between CHCl3 and H2O. The pH of the aqueous layer was adjusted to ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na2SO4 and solvent removed affording the title compound (0.42 g, 1.60 mmol, 95%) which was used without further purification: LC-MS (ES) m/z=249 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:33]1([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:38])[NH:22][C:9]4[CH:10]=[C:11]([C:14]5[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(-n4ccnc4)c2)=N3)cc1

Procedure:
Prepared from {4′-cyano-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example K41) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (128 mg).
Reaction SMILES: [CH2:1]1[CH2:14][N:13]2[C:4]3[C:5]([CH2:10][CH2:11][CH2:12]2)=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=3[CH2:2]1.[CH3:15][C:16]([CH3:25])([CH3:24])[C:17](=O)[CH2:18][C:19](OC)=[O:20]>ClCCl>[CH3:15][C:16]([C:17]1[O:9][C:6]2[C:7](=[CH:8][C:3]3[CH2:2][CH2:1][CH2:14][N:13]4[C:4]=3[C:5]=2[CH2:10][CH2:11][CH2:12]4)[C:19](=[O:20])[CH:18]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: Oc1ccc2c3c1CCCN3CCC2
Solvent: ClCCl
Product: CC(C)(C)c1cc(=O)c2cc3c4c(c2o1)CCCN4CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
8-Hydroxyjulolidine (1.0 g, 5.29 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (1.0 g, 6.32 mmol) were heated together under nitrogen at 200° C. for 4 hours, after which time more methyl 4,4-dimethyl-3-oxopentanoate (0.5 g, 3.16 mmol) was added and heating was continued for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in dichloromethane and applied to a short column of silica gel (approx. 200 g). Elution with dichloromethane removed non-polar by-products, while subsequent elution with ether afforded 11-[1,1-dimethylethyl]-9-oxo-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizine (1.12 g, 71% yield) as a brown oil which solidified on standing. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].OS(O)(=O)=O>O.C(O)C>[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]([OH:10])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1ccccc1OC(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC(O)c1ccccc1OC(F)F
Reaction time: 0.33 h

Procedure:
7.2 g of potassium cyanide were dissolved in 30 ml of water and 6 ml of ethanol, while cooling. 16 g of 2-difluoromethoxybenzaldehyde were then added at 0°-5° C., while cooling. After subsequently stirring the mixture between 0° and 10° C. for 20 minutes, a mixture of 7 ml of concentrated H2SO4 and 18 ml of water was added dropwise. The mixture was subsequently stirred for a further 2 hours and was thereby allowed to come to room temperature. After extracting twice with methylene chloride, the organic phase was dried and the solvent was distilled off. 2-Difluoromethoxy-α-cyano-benzyl alcohol was obtained as a colorless oil, the structure of which was confirmed by a nuclear magnetic resonance spectrum. The yield was virtually quantitative.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>ClCCl.O>[C:16]([N:6]1[CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CC[C@@H](C(=O)O)NC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C[C@@H](C)CC[C@H]1C(=O)O
Reaction time: 72 h
Yield: 97.8 %

Procedure:
15.9 g (111 mmol) of the (2S*,5S*)-5-methylpiperidine-2-carboxylic acid described above was dissolved in 220 ml of a dichloromethane/water (1:1). 93.3 g (1.11 mol) of sodium hydrogencarbonate and 21.0 ml (222 mmol) of acetic anhydride were added thereto in this order at room temperature, followed by stirring for 3 days. The reaction solution was poured into 6N-hydrochloric acid under cooling with ice, and the extraction with chloroform was conducted. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure to give 20.1 g of the title compound as a colorless oil. Yield 98%.
Reaction SMILES: [CH2:1]([O:5][CH:6]([CH3:12])[C:7](N(C)C)=[O:8])[CH2:2][CH2:3][CH3:4].[CH2:13]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH3:16].CNC.C([C@H:29]1[CH2:34][CH2:33][C@H:32](C2C=CC([Mg]Br)=CC=2)[CH2:31][CH2:30]1)CC>C1COCC1>[CH2:13]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:14][CH2:15][CH3:16].[CH2:1]([O:5][CH:6]([C:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCC[C@H]1CC[C@H](c2ccc([Mg]Br)cc2)CC1
Reactant: CCCCOC(C)C(=O)N(C)C
Agent: CCCCOC(C)C(=O)O
Agent: CNC
Solvent: C1CCOC1
Product: CCCCOC(C)C(=O)c1ccccc1

Procedure:
To (R) 2-butoxy-N,N-dimethylpropanamide prepared from (R) 2-butoxypropionic acid and dimethylamine, a solution of 4-(trans-4'-propylcyclohexyl)phenylmagnesium bromide in THF is dropped. They are reacted and purified in the same manner as in Example 3 (1) to obtain (R) 4-trans-4'-propylcyclohexyl)phenyl (1-butoxyethyl) ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 300 g of 3,4-dichlorocinnamic acid (J. Org. Chem., 26:2991 (1961)) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 3,4-dichlorocinnamic acid methyl ester, mp 114°-15° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:40])([C:34]2[O:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:33])([C:34]3[O:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[CH3:40])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(C)(C)CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)o1
Yield: 92 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 125b (1.3 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a brown solid (1.3 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][O:15]3)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[OH:15][CH:14]([C:12]1[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=1)[CH2:16][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C3CO3)c2)cc1
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)CN3CCOCC3)c2)cc1
Temperature: 50 °C

Procedure:
Into a 20 mL reaction vessel were combined 4′-methyl-N-((6-methylpyridin-3-yl)methyl)-5-(oxiran-2-yl)biphenyl-3-carboxamide (15 mg, 0.042 mmol), ethanol (2 mL), and morpholine (13 mg, 0.15 mmol). The mixture was heated at 50° C. overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 100 mg 4-Amino-benzoic acid in 1 mL DCM and 0.2 mL NEt3, 62 mg piperidine and 184 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent amide coupling reaction without further purification. Yield: 125 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](C)=[CH:9][C:8]([CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:7](Br)[N:6]=1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:7]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c(C2CCOC2)cc1C
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Yield: 363.1 %

Procedure:
A solution of methyl 6-bromo-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (0.185 g, 0.65 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.15 g, 0.96 mmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride methylene chloride complex (CAN 95464-05-4, 20 mg) and cesium carbonate (CAN 534-17-8, 0.63 g, 2 mmol) in DMF (10 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. After filtration, the reaction mixture was poured into water (20 mL) and washed with ethyl acetate (2×20 mL). The organic layer was concentrated in vacuo to provide the title compound (0.75 g, 73%) as black oil which was used in the next step without further purification; MS (EI): m/e=318.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)C>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[O:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCO)ccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-5-(2-hydroxyethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.07 g, Example 66a) in anhydrous dichloromethane (20 ml) was added Dess-Martin periodinane reagent (1.95 g) and the mixture was stirred at room temperature for 1 h. Sodium thiosulfate (3.43 g) was dissolved in aqueous sodium bicarbonate solution (28 ml) and added to the reaction mixture. Diethyl ether (50 ml) was then added and the mixture was stirred for 10 min. The layers were partitioned and the organic layer was washed with water then brine. The organic extracts were then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the subtitle compound as a white solid (1.06 g).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].[F-].C([N+:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])CCCC)CCC>O1CCCC1>[OH:1][CH2:17][C:16]1[CH:15]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:9][CH2:14][CH:15]1[CH2:16][CH2:17][C:18](=[O:2])[NH:9][C:14]1=[O:3]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CCC(CNc2ccccc2CO)C(=O)N1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
5 ml of a 1 M solution of tetrabutyl ammonium fluoride trihydrate in tetrahydrofuran were added to a solution of 0.20 g of the product from step 1 in 5 ml tetrahydrofuran. It was stirred for 3 h at 20° C., evaporated in vacuo and the residue was purified by flash chromatography on silica gel with ethyl acetate as eluent. 0.12 g (85% of theoretical) of the title compound were obtained in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:27]=[N-:28]
Reactant: CCCCC(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 114.5 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(2-methanesulfonyloxyethoxy)phenyl]propionate (1.65 g), which is the product of Reference example 6(f), and sodium azide (0.95 g) and the reaction mixture was treated to afford the desired compound (1.62 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:31])=[C:17]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:16]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C#N)sn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
To a solution of (R)-3-(benzyloxy)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (73 mg, 0.18 mmol) in DMSO (2 mL), K2CO3 (200 mg, 1.44 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 90 C for 15 min, the mixture was purified by HPLC to give the titled compound (6 mg). MS 426.3 (M+H); UV 200.4, 293.4 nm
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl-].[Cl-].[Cl-].[Al+3].[C:17](Cl)(=[O:19])[CH3:18].Cl.[OH-].[Na+]>O.ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Cl)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 24.3 %

Procedure:
A mixture of 5-chloro-8-quinolinol (6.67 g, 37.1 mmol, from Aldrich), aluminum trichloride (20.00 g, 150.0 mmol), and acetyl chloride (12.1 mL, 170 mmol) was stirred at 0° C. for 4 hours, then heated at 130° C. for 12 hours, cooled, and decomposed with water (39 mL) (caution!) and conc. HCl (13 mL). The solid product was filtered, and dried under reduced pressure. The solid obtained was then dissolved in 50 mL of water. To the solution was added 100 mL of dichloromethane. The mixture was cooled with an ice bath and its pH was adjusted to 4 with 20% NaOH. The mixture was filtered under reduced pressure. The solid collected was washed with water and air dried to give the desired product (˜2 g). The layers of the filtrate were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated to give additional desired product (total 5.6 g, 68%). LCMS calculated for C11H9ClNO2 (M+H)+: m/z=222.0; Found: 222.0.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[N:19]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: Cc1cc(Oc2ccc(OC(F)(F)F)cc2)nc(Cl)n1
Yield: 60 %

Procedure:
Prepared in analogy to example 81a) from 4-trifluoromethoxyphenol and 2,4-dichloro-6-methylpyrimidine in a yield of 60%. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.28 (d, 2H), 7.18 (d, 2H), 6.65 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:12][N+:13]([O-:15])=[O:14])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26](Cl)=[O:27]>>[NH2:1][C:2](=[N:12][N+:13]([O-:15])=[O:14])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH:8][C:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)=[O:27]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Yield: 64 %

Procedure:
Prepared analogously to Example 4a) from (R)-N5 -[amino(nitroimino)methyl]-ornithine and 2-naphthoylchloride in a yield of 64% of theory. Colourless crystals which were used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C#N)CC1
Yield: 79.9 %

Procedure:
In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60% ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80%).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:30])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH2:1]([N:8]([C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Yield: 56.5 %

Procedure:
2(S)-(N,N-Dibenzylamino)-1-phenyl-3-oxo-6-methylheptane (100 g) was dissolved in a mixture of methanol (500 ml) and tetrahydrofuran (500 ml), and the solution was cooled to -20° C. To the solution was portionwise added sodium borohydride (63 g) at said temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (500 ml) and water (500 ml) were added to the residue for extraction. The water layer was re-extracted with ethyl acetate (250 ml ). The combined organic layer was washed with saturated brine (500 ml), and the organic layer was concentrated. Water (100 ml) was added to the residual oily substance, and azeotropic distillation was performed. After 8 times of azeotropic distillation, toluene (100 ml) was added. Additional azeotropic distillation gave 2(S)-(N,N-dibenzylamino)-1-phenyl-3(S)-hydroxy-6-methylheptane (56.8 g).