Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]([CH:28]1[CH2:30][CH2:29]1)([CH3:27])[CH2:23][C:24]([NH2:26])=[O:25]>>[NH2:26][C:24](=[O:25])[CH2:23][C:22]([NH:21][C:12](=[O:14])[C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]2([F:1])[CH2:3][CH2:4][CH2:5]2)=[CH:11][N:10]=1)([CH:28]1[CH2:30][CH2:29]1)[CH3:27]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Reactant: CC(N)(CC(N)=O)C1CC1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 49%); MS (ESI, m/z): 418.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.CC(C)=[O:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[CH3:28][S:25]([O-:31])(=[O:27])=[O:26]
Reactant: CC(C)=O
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Product: CS(=O)(=O)[O-]
Reaction time: 0.05 h

Procedure:
The m-AMSA methanesulfonate salt was prepared by slurrying 1 g of m-AMSA base in 125 ml of acetone for 20 minutes. The resulting near solution was vacuum filtered to remove undissolved solids. The solids remaining in the filter were washed with 10 ml of acetone and the wash solution was added to the original filtrate. To the above solution of m-AMSA base there was added with rapid stirring 0.24 ml of methanesulfonic acid over a three minute interval. Crystals formed and the mixture was stirred five additional minutes. The crystals were then vacuum filtered, washed with two 20 ml portions of acetone and vacuum dried at 50° C. for 24 hours to give 1.18 g of m-AMSA methanesulfonate (1:1) salt.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]([C:14]([O:16]C)=[O:15])[N:7]=1>Br>[C:14]([C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])[C:11]([OH:12])=[CH:10][CH:9]=1)([OH:16])=[O:15]
Reactant: COC(=O)CCc1nc(C(=O)OC)ccc1OC
Agent: Br
Product: O=C(O)CCc1nc(C(=O)O)ccc1O
Yield: 75.6 %

Procedure:
Under the conditions of example 16K, 6.5 g of 3-(3-methoxy-6-methoxycarbonyl-2-pyridyl)-propionic acid methyl ester in 60 ml of 48% hydrobromic acid is reacted and worked up. 4.1 g of 3-(6-carboxy-3-hydroxy-2-pyridyl)-propionic acid of melting point 210°-212° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3]1.C(OCC)(=[O:24])C>C1CCCCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N+:9]=3[O-:24])[C:5]=2[CH:15]=1)#[N:20]
Reactant: Cc1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)nc1
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Product: Cc1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]([O-])c1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(5-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-methylpyridine N-oxide of melting point 151°-153° C. (from ethyl acetate and cyclohexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[S:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1)(=[O:20])=[O:18]
Reactant: CCOC(=O)CC1(c2ccc(O)cc2)COC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)COC1

Procedure:
To a solution of ethyl 2-[3-(4-hydroxyphenyl)oxetan-3-yl]acetate (500 mg, 2.12 mmol), TEA (321 mg, 3.17 mmol), and DCM (40 mL) was added dropwise a solution of Tf2O (658 mg, 2.33 mmol) in DCM (20 mL) in 15 min at −5° C. (ice/salt bath). After stirring for an hour, the reaction was quenched by the addition of water (50 mL). The crude mixture was extracted with DCM (2×40 mL). The organic layers were combined and concentrated to a residue which purified by flash column chromatography on silica gel (1-5% EtOAc/petroleum ether) to afford compound 67a as white oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H15F3O6S: 369.3 (M+H). found: 369.1.
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH3:14])[C:3]1=[O:15]>[Ni]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:14])[C:3](=[O:15])[C:2]2([F:16])[F:1]
Reactant: CN1C(=O)C(F)(F)c2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Product: CN1C(=O)C(F)(F)c2cc(N)ccc21

Procedure:
3,3-Difluoro-1-methyl-5-nitro-1,3-dihydro-2H-indol-2-one was subjected to a hydrogenation reaction using a Raney-Ni catalyst under a hydrogen stream to obtain 5-amino-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH2:1]([N:3]([CH:22]([CH3:24])[CH3:23])[C:4]1[CH:21]=[N:20][C:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=1)[CH3:2].C(OCC)(=O)C.[ClH:31].C(=O)([O-])O.[Na+].Cl>C(OCC)(=O)C>[ClH:31].[CH2:1]([N:3]([CH:22]([CH3:23])[CH3:24])[C:4]1[CH:21]=[N:20][C:7]2[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCN(c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(c1cnc2c(n1)OCCNC2)C(C)C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-[ethyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (10 mg) in ethyl acetate (0.1 mL) was added 4 N hydrogen chloride-ethyl acetate solution (0.5 mL), and the mixture was stirred for 30 min. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. To a solution of the obtained crude product in methanol (0.5 mL) was added 1.0 N hydrochloric acid (33 μL), and the mixture was stirred for 5 min. The reaction mixture was concentrated, and the obtained crystals were purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (10 mg, 100%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[O:26][CH2:27][CH2:28]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: COc1ccc(OCCO)cc1OC
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3,4-dimethoxyphenoxy)ethanol (1.65 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-diethyl ether, 99:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-(3,4-dimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:18][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Temperature: 60 °C
Yield: 89 %

Procedure:
To a solution of (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate (5.0 g, 12.47 mmol) in ethanol (41.6 mL) was added hydrazine hydrate (6.06 mL, 125 mmol). The reaction mixture was heated at 60° C. for 2 h. The reaction mixture was filtered through Celite pad. The filtrate was concentrated and the residue was diluted with DCM and filtered off through Celite. The same process was repeated until no white precipitate was shown. To remove the white side product completely, the product was dissolved in 1N HCl (30 mL), washed with EtOAc, and the aqueous phase was neutralized to pH 7 then back-extracted by EtOAc. The organic was dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (89%). LCMS (m/z): 271.1 (MH+), 0.58 min.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2o1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc3ccccc3o2)CC1

Procedure:
To 3.08 g of 2-chlorobenzoxazole was added 200 ml of N-methylpiperazine under cooling with ice, followed by 2 hours of reaction at the same temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 200 ml of ethyl acetate, washed with water, dehydrated with MgSO4 and then concentrated to dryness under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain 2.77 g of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[N:31]=[CH:30][C:29]([CH2:32][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(N2CCOCC2)nc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(N5CCOCC5)nc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-morpholin-4-ylpyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-morpholin-4-ylpyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][N:6]1[CH:14]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:24])[CH3:2].S(=O)(=O)(O)O.[C:32](=O)([O-])O.[Na+]>CO>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:14]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([O:19][CH3:32])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:24])[CH3:26]
Reactant: O=C([O-])O
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)OC

Procedure:
To a solution of 0.53 g of Compound 27 in 5 ml of methyl alcohol was added 0.2 ml of conc. sulfuric acid. After heating at reflux for 2 hours, pH was adjusted to 7 with sodium hydrogencarbonate. The mixture was concentrated under reduced pressure. After 30 ml of water and 30 ml of methylene chloride were added to the residue, pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure to give 0.14 g of methyl 2-[2-(2-diethylaminoethyl)isoindolin-1-on-3-yl]benzoate (Compound 28).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[OH:26]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[O:26][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:20][C:4]1[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:1][CH2:2][C:3]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Product: Brc1ccc2[nH]c3c(c2c1)COc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using chroman-4-one (3.21 g, 21.7 mmoL) and 4-bromo-phenylhydrazine HCl salt (5.33 g, 23.8 mmoL) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32]CC2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OCC2C=CC=CC=2)=O)=CC=1)([O-])=O>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(OCc3ccccc3)=CS[C@H]12
Agent: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OCc3ccccc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The isomer mixture obtained, consisting of 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of about 3:1, is dissolved in 8 ml of trifluoroacetic acid and the solution is stirred for 90 minutes at room temperature. The reaction mixture is then concentrated by evaporation in vacuo and residual trifluoroacetic acid is repeatedly driven off with toluene. The residue is chromatographed on 20 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), giving 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colourless foam. IR spectrum (methylene chloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and 8.3 μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, J=17 Hz), 4.57 (2H, s), 5.06 (1H, d, J=5 Hz), 5.35 (2H, AB q, J=14 Hz), 5.7 (1H, dd, J=5, 10 Hz), 6.8-8.4 (10H, c), 11.4 (1H, br.s.) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[Br:14])([O-])=O>CCO.CC(O)=O.O1CCOCC1.O.Cl.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[Br:14]
Reactant: O=[N+]([O-])c1cccc2c(Br)cccc12
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc2c(Br)cccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 135.1 %

Procedure:
To the solution of 5-nitro-1-bromonaphthalene (A) (2.5 g, 10 mmol) in EtOH/AcOH /Dioxane/H2O (2:2:2:1) (30 mL) was added Fe (5.6 g, 100 mmol) and 2 drops of 2 N HCl. The reaction mixture was stirred at 100° C. for 2 hrs. After evaporation of solvent, the residue was dissolved in 100 mL DCM and washed with 5% NaHCO3 (3×30 mL) and dried over Na2SO4. After evaporation of solvent, the crude mixture was purified on a silica gel column, eluting with DCM/hexanes (1:1), to give compound B as a white powder (3.0 g, 97%). mp 65-66° C.; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.0, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.2 Hz, 1H), 6.83 (d, J=7.2 Hz, 1 H), 4.18 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 142.5, 133.0, 130.4, 128.0, 125.1, 125.0, 123.9, 121.0, 118.4, 110.9; ESI-MS (m/z) calcd. for C10H9BrN222.0 (M+H)+, found 222.1. Anal. Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31. Found: C, 53.81; H, 3.46; N, 6.11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and piperidine (3.51 ml, 35.6 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.94 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:15][CH2:14][C@H:13]([O:16][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[S:31][CH:32]=2)[N:3]=1.F>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)[S:31][CH:32]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Agent: F
Solvent: CC#N
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25 mg (0.04 mmol) of the compound from Example 13A (trans isomer) are dissolved in 1 ml of dry acetonitrile, and 0.1 ml (2.30 mmol) of 40% strength hydrofluoric acid is added. The reaction mixture is stirred at RT for 2 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[OH:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2ccccc2OC)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
2.63 g of (4-methoxyphenyl)(2-methoxyphenyl)methanol 51 are dissolved in dichloromethane, and 5.03 g of Dess-Martin reagent are added. The mixture is stirred at room temperature for 2 h. Then 20% Na2SO3 and NaHCO3 solution are added, and the mixture is extracted with diethyl ether. The organic phase is extracted with saturated NaCl solution and dried over sodium sulfate. The solution is concentrated in vacuo and purified by column filtration. 2.61 g of 52 are obtained. C15H14O3 (242.28) MS (ESI+) 243.04 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([F:15])[F:14])[CH2:5]2.[CH3:16]B1OB(C)OB(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O1CCOCC1>[F:14][CH:13]([F:15])[CH2:12][N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:16])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1c2ccc(Br)cc2CN1CC(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)CN(CC(F)F)C2=O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
The compound (5.77 g, 20.9 mmol) of step B, trimethylboroxine (3.00 ml, 21.6 mmol), bis(tricyclohexylphosphine)palladium(II) dichloride (1.53 g, 2.07 mmol) and 1.27 mol/l aqueous potassium phosphate solution (50 ml, 63.5 mmol) were added to 1,4-dioxane (200 ml), and the mixture was heated under reflux for 110 min. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (NH silica gel use, ethyl acetate-hexane) to give the title compound (4.39 g, yield 99%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25]O)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][F:27])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CF)CC1
Yield: 24.3 %

Procedure:
A mixture of (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (41 mg), perfluoro-1-butanesulfonyl fluoride (62 mg), triethylamine (62 mg) and triethylamine.trishydrofluoride salt (33 mg) in tetrahydrofuran (1 mL) was stirred 24 h at room temperature. The mixture was then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl:acetate (3:1 to 1:1 v/v) as eluant to afford the title compound (10 mg, 24%) as a colorless solid. MS (EI): 403.3 (M+H)+.