Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[OH-].[Na+].O1CCCC1>O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8](=[O:10])[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 50 °C
Yield: 84.8 %

Procedure:
A suspension of 7.12 g (20.7 mmol) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 10.3 ml of a solution of sodium hydroxide (1N) is prepared and tetrahydrofurane is added until a clear solution is obtained. The mixture is heated to 50° C. for 1 hour. For the working-up, the tetrahydrofurane is evaporated under reduced pressure. The white suspension obtained is diluted with water, then filtered. The white product is treated with toluene and evaporated under reduced pressure to remove most of the water. The azetropic distillation is repeated three times. There are obtained 5.78 g (85% of theory) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([CH:31]([F:33])[F:32])=[CH:28][C:29]#[N:30]>CC(O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[CH:31]([F:33])[F:32])#[N:30]
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#CC=C(N)C(F)F
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C(F)F)N1

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 285 mg (2.41 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 176 mg (67% of th.) of the racemic title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([NH2:38])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:24]1[CH:23]=[C:22]([CH3:21])[CH:27]=[C:26]([CH3:28])[CH:25]=1)=[CH:37]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(C)cc(-c2cc3cc(N)ccc3[nH]2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2cc3cc(NC(=O)OCc4ccccc4)ccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(3,5-dimethylphenyl)-5-amino-1H-indole (1.16 g in 60 mL dry methylene chloride) at −60 ° C. was added 0.86 mL benzyl chloroformate followed by 1 mL diisopropylethylamine and the mixture warmed slowly to 0° C. After 45 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with methylene chloride. The organic portion was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (hexane:methylene chloride:ethyl acetate, 8:8:1; then 7:7:1) gave the title compound (1.68 g).
Reaction SMILES: C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:10])=O.[NH:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[CH:14]1>CN(C)C=O>[Cl:10][C:17]1[C:16]2[N:15]=[CH:14][NH:13][C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: [O-][n+]1cc2nc[nH]c2c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1nc2ccccc2c2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of toluene (0.45 ml/mmol) and dimethylformamide (0.90 ml/mmol) was cooled in an ice-bath and phosphorus oxychloride (2.6 eq.) was added. After 10 minutes the appropriate 1H-imidazo[4,5-c]quinolin-5-oxide was added and the solution was stirred at room temperature for 10 minutes. Subsequently the solution was heated to 100° C. on a steam bath for 30 minutes. Upon cooling, the solvent was evaporated and the resulting syrup was poured over crushed ice while stirring. The mixture was then warmed to room temperature and carefully adjusted to pH 6-7 with solid NaHCO3. After 2 hours, the solid that was formed was filtered off, washed with water and diisopropylether and subsequently dried.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][CH2:26][OH:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][O:27][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: OCCN1CCOCC1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCN1CCOCC1

Procedure:
The title compound, white solid, m.p.=135-137° C. and MS: m/e=369.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2-morpholin-4-yl-ethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cccc(F)c3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound is prepared by hydrolysis of 23h using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 85.7 %

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 85.7% of theoretical, Melting point: 163°-165° C. C29H30N4O3 (470.58) Calculated: C 71.46, H 6.42, N 11.91 Found: 71.33, 6.64, 11.74
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.O>CS(C)=O>[CH3:14][C:9]1[C:10](=[O:13])[NH:11][CH2:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH3:18])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Reactant: Cc1ncc[nH]1
Solvent: CS(C)=O
Solvent: O
Product: CC1=C(c2ccc(-n3ccnc3C)c([N+](=O)[O-])c2)CNC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluoro-3-nitrophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one (6.5g, 28 mmol) and 2-methylimidazole (6.8 g, 83 mmol) are combined in dimethylsulfoxide (50 mL) and the mixture is heated to 50° C. under a nitrogen atmosphere for 4 hr. The mixture is then cooled to room temperature, and water is added to give a precipitate. The mixture is kept cold for 1 hr, and the precipitate is collected by filtration, washed with water, and air-dried to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[NH4+].[Cl-].O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(c2ccc(O)cc2)=NN1c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
The product from step 1 (1.25 g, 4.4 mmol) in DCM (30 mL) was added BBr3 (30 mL, 1 M in DCM) dropwise at 0° C. After stirring 4 h at rt, the mixture was cooled to 0-5° C. on an ice-bath while saturated NH4Cl solution (30 mL) was added dropwise. Additional water was added and the DCM was removed at reduced pressure. The solid was collected and dried to give 1.1 g (93%) of a tan solid; Mp>220° C.; MS m/z 268 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH2:15]1COCC1>C(OCC)C>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(F)ccc1Br
Solvent: CCOCC
Product: CC(=O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a solution of 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide (1.54 g, 5.88 mmol) in THF (60 mL) at 0° C. was added McMgI (3.0 M in diethyl ether, 1.998 mL, 5.99 mmol) dropwise over 5 min, the reaction immediately turned bright yellow after a few drops and then after continued addition the reaction lost the yellow color and a significant amount of white precipitate crashed out. After 15 min the reaction was warmed to room temperature and stirred for 15 h after which an additional 3×0.5 equiv. McMgI (1.0 mL) was added every 3 h until after 23 h the reaction was quenched by addition of sat. aq. NH4Cl solution and extracted with diethy ether (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Hexanes) to afford 1-(2-bromo-5-fluorophenyl)ethanone (1.038 g, 4.78 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.57 (dd, J=8.8, 4.9 Hz, 1H), 7.18 (dd, J=8.4, 3.1 Hz, 1H), 7.07-6.99 (m, 1H), 2.63 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:15])[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)O)C1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.1 %

Procedure:
A mixture of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoic acid (100 mg, 0.34 mmol), morpholine (29 mg, 0.34 mmol), DCC (77 mg, 0.37 mmol), and DMAP (46 mg, 0.37 mmol) in dry DCM (2.5 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rota vapor to obtain 10 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinopropan-1-one as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:19][S:20]([C:23]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:21].Cl>O1CCCC1>[ClH:19].[N:4]1([CH2:3][CH2:2][NH:1][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:21])=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCCN1CCCCC1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCCCC1

Procedure:
A solution of 1-(2-aminoethyl)piperidine (0.23 g, 1.79 mmol) and N,N-diisopropylethylamine (0.23 g, 1.79 mmol) in tetrahydrofuran (5 ml) is added over 15 minutes to a stirred solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (0.50 g, 1.79 mmol) in tetrahydrofuran (25 ml) cooled with an ice bath. The product is isolated following the procedure of Example 1 and converted to the hydrochloride salt with anhydrous ethanolic hydrogen chloride.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][OH:13])(=[O:8])=[O:7])C.Cl[C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1>>[CH2:16]([C:11]([CH2:14][CH3:15])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][O:13][C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1)[CH3:17]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CCC(CC)(CO)CCS(=O)(=O)N=CN(C)C
Product: CCC(CC)(CCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-butanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 148°-149° C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nccn2c(C3CCC3)nc(/C=C/c3ccccc3)c12
Temperature: 75 °C

Procedure:
A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.159 mmol), styrene (0.022 mL, 0.191 mmol) and triethylamine (0.044 mL, 0.318 mmol) in DMF (3.0 mL) was degassed three times, charged with tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0159 mmol) degassed twice more and then heated at 75° C. for 16 h. The reaction mixture was then concentrated in vacuo dissolved in MeOH/CH3CN (1:1)(4 mL) and was filtered through a 0.45 μM fritted autovial prior to purification via mass directed preparative HPLC which afforded the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 1.87-1.99 (m, 1H), 2.02-2.17 (m, 1H), 2.37-2.47 (m, 4H), 3.18 (s, 2H), 3.83-3.94 (m, 1H), 6.94 (d, J=4.9 Hz, 1H), 7.25 (t, J=7.33 Hz, 1H), 7.32-7.40 (m, 3H), 7.45 (d, J=15.5 Hz, 1H), 7.63 (d, J=15.45 Hz, 1H), 7.73 (d, J=7.46 Hz, 2H); MS (ES+): m/z 291.15 [MH30 ].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CC(C)([O-])C.[K+]>CC(O)(C)C.O>[CH:4]1([S:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 79 %

Procedure:
To a solution of methyl 4-(3-chloropropylsulfonyl)benzoate (1.89 g, 6.83 mmol) in 2-methylpropan-2-ol (20 mL) was added potassium tert-butoxide (1.53 g, 13.7 mmol) and the slurry heated at 80° C. for 10 min. Additional 2-methylpropan-2-ol (20 mL) was added to facilitate stirring and the heating continued for 25 min. The reaction mixture was diluted with water (100 mL) and washed with ethyl acetate (3×100 mL). The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed in vacuo to provide 4-cyclopropylsulfonylbenzoic acid (1.22 g, 79%) as a beige solid. ESI-MS m/z calc. 226.0. found 227.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[ClH:32]>C(OCC)(=O)C>[NH2:1][C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[ClH:32]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Boc-Asp(OMe)-Pro-OBzl (7.25 g) was dissolved in dry ethyl acetate (25 ml) and cooled in ice. Ethyl acetate saturated with hydrochloric acid (45 ml) was added and the mixture was stirred at 0° C. for 5 h. The excess of hydrochloric acid was removed by a nitrogen-flow and the resulting solution was concentrated in vacuo yielding H-Asp(OMe)-Pro-OBzl.HCl as a white solid (6.21 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (307 mg, 1 mmol), iron powder (196 mg, 3.5 mmol), acetic acid (0.4 mL, 7 mmol) and methanol (5 mL) is heated at 66 C until no nitro compound left. After it is dried it is treated with ethyl acetate and water, and filtered through a pad of celite. The ethyl acetate layer is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and then dried to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO.Cl>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (140 mg, 0.41 mmol) and N,N-diisopropylethylamine (320 μl, 2.07 mmol) in N,N-dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (235 mg, 0.61 mmol) and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Hydroxylamine hydrochloride (113 mg, 0.61 mmol) was then added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into hydrochloric acid (1M, 20 ml) and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99.5:0.5) gradually changing to dichloromethane:methanol (97:3) to afford the title compound as a yellow oil (62 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+].O>[C:17]1([CH2:16][O:15][C:13]([NH:1][CH2:2][CH:3]2[CH2:4][CH2:5][CH:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCC1CCC(C(=O)O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 63.6 mmol, Aldrich) in 2N aqueous NaOH (65 ml) at 0° C. was added benzyl chloroformate (11.9 g, 70 mmol, Aldrich) and the reaction temperature was maintained below 10° C. The cloudy mixture was stirred at RT for 0.5 h. It was then diluted with H2O (100 ml). The clear solution was washed with ether (3×80 ml). The pH of the aqueous layer was adjusted to 2 by adding 6N HCl. The precipitates were filtered and dried in vacuo. 17.8 g of 23 was obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=1>>[F:17][C:6]1[C:7]2[C:12](=[CH:11][C:10]([F:16])=[CH:9][CH:8]=2)[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][N:21]=2)=[CH:14][C:5]=1[CH2:4][C:3]([OH:2])=[O:18]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Reactant: CCS(=O)(=O)c1ccc(Br)nc1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)c(F)c3ccc(F)cc23)nc1
Yield: 12.4 %

Procedure:
Starting with (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (50 mg, 0.198 mmol) and 2-bromo-5-ethanesulfonyl-pyridine (52 mg, 0.208 mmol), using a method analogous to the one described for example 4-1, [1,6-difluoro-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid (10 mg, 12%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, 1H), 8.34 (dd, 1H), 8.19 (dd, 1H), 7.42-7.76 (m, 4H), 3.78-3.86 (m, 2H), 3.37-3.40 (m, 2H), 1.12 (t, 3H); MS cald. for C19H15F2NO5S 407, obsd. (ESI+) [(M+H)+] 408.