Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22]I>CN(C=O)C>[Cl:19][CH2:20][CH2:21][CH2:22][S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: O=S(O)c1ccc(F)c(F)c1
Reactant: ClCCCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(CCCCl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmol triethylamine in 100 ml DMF was added 70.7 mmol 1-chloro-3-iodopropane and the mixture stirred at RT for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:23])[N:13]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH:15]([C:16](O)=[O:17])[C:5]2=1.[CH3:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:23])[N:13]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH:15]([C:16]([N:25]([CH3:26])[CH3:24])=[O:17])[C:5]2=1
Reactant: COCCN1CC(C(=O)O)c2c(n(C)c3ccc(Cl)cc23)C1=O
Reactant: CNC
Product: COCCN1CC(C(=O)N(C)C)c2c(n(C)c3ccc(Cl)cc23)C1=O

Procedure:
The preparation is carried out as in Example 1.5, from 8.3 g (26 mmol) of (±)-6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and from dimethylamine. 8.6 g of product are isolated, which product is recrystallized from propan-2-ol. 6.9 g (19 mmol) of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[O:6][CH:7]([OH:10])[CH2:8][CH3:9])([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:5]=1[O:6][CH:7]([OH:10])[CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCC(O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: CCC(O)Oc1ccc(N)cc1N

Procedure:
0.039 mol (9.5 g) of (2,4-dinitro) phenoxypropanol in 30 cm3 of absolute alcohol are reduced on Pd/C at 10% in a bomb under 25 kg of pressure of hydrogen at 70° C. for 1 hour.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CS(C)=O.CO>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Yield: 6.3 %

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol), 4-methylstyrene (239 mg, 2.3 mmol) and NaH (120 mg, 60% dispersion in oil, 3 mmol) were heated in DMSO (4 mL) at 120° C. overnight (16 h) after which methanol was added and the contents were concentrated to dryness. The resulting crude product was purified 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) and/or silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient to obtain 20 mg (6.2% yield) of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 13.3 (bs, 1H), 7.4-7.0 (m, 5H), 6.80-6.70 (d, 2H), 4.7-4.6 (d, 1H), 4.40-4.22 (m, 1H), 4.20-4.10 (m, 1H), 4.10-4.0 (d, 1H), 3.5-3.4 (t, 1H), 3.20-3.17 (t, 1H), 3.0 (t, 2H), 2.80 (s, 3H), 2.7-2.61 (m, 1H), 2.40 (s, 3H), 2.23 (s, 3H), 2.2-2.1 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[NH:26][C:25]2=[O:35])=[C:10]([F:36])[CH:9]=1.[N+:37](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:37][N:26]1[C:27]([C:31]([F:33])([F:34])[F:32])=[CH:28][C:29](=[O:30])[N:24]([C:11]2[CH:12]=[C:13]([O:14][C:15]3[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]([Cl:7])=[CH:9][C:10]=2[F:36])[C:25]1=[O:35]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ncccc2[N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A suspension of potassium carbonate (0.23 g), 3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.5 g) and 2,4-dinitrophenoxyamine (0.32 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 2:98. The product was isolated as a yellow semi-solid (0.3 g), mp 90-6° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc([N+](=O)[O-])cc32)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(N)cc32)cc1
Yield: 38.9 %

Procedure:
3-Methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (750 mg, 2.26 mmol) was dissolved in 30 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 Hexanes/Ethyl Acetate) to give 3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (265 mg, 38.9%) as a light tan crystalline solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:16][CH:17]=2)=[O:11])=[CH:2]1.[BH4-].[Na+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)=[CH:16][CH:17]=2)[OH:11])=[CH:2]1
Reactant: O=C(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Reaction time: 1 h

Procedure:
To (1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone 73 in ethanol was added sodium borohydride. After one hour, the reaction was quenched with water and extracted with ethyl acetate. The organic portion was dried with magnesium sulfate and concentrated to provide (1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol 74, which was used in the next step without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:30][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:39])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Solvent: ClCCl
Product: COc1ccc(C(=O)[NH+]([O-])c2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Reaction time: 12 h
Yield: 29.3 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide (0.215 gm, 0.49 mmole) (Example 4) was suspended in dichloromethane. To this reaction mixture was added 0.507 gm (2.9 mmoles) of meta-chloroperbenzoic acid (50%) and reaction mixture was refluxed for 3 hours and stirred at room temp. for 12 hours. Dichloromethane was removed under vacuum and the crude compound was purified through silica gel column to obtain 0.066 gm (30%) of the N-oxide.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:39]O)[C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:39]=[C:21]([C:22]3[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[N:20]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C(N)=NO)c1
Product: COCc1cc(-c2nc(-c3cccc(COCCC(=O)OC(C)(C)C)c3)no2)ccc1N1CCCCC1C

Procedure:
Tert-butyl 3-[(3-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}benzyl)oxy]propanoate was prepared following the general procedure 3 starting from Intermediate 2 and Intermediate 20. It was hydrolyzed following general procedure 8 to afford the title compound as a pale yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (m, 1H), 8.06 (m, 3H), 7.57 (m, 2H), 7.39 (m, 1H), 4.60 (s, 2H), 4.57 (m, 2H), 3.70 (t, J=6.2 Hz, 2H), 3.42 (s, 3H), 3.24 (m, 1H), 3.03 (m, 1H), 2.63 (m, 1H), 2.54 (t, J=6.2 Hz, 2H), 1.85-1.30 (m, 6H), 0.86 (d, J=6.1 Hz, 3H). LC/MS (Method B): 466.4 (M+H)+, 464.4 (M−H)−. HPLC (Method A) Rt 3.30 min (Purity: 98.3%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)OCCO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([N:9]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.67 h

Procedure:
A mixture of 31.3 g 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-benzamide, 5.6 g of 55% sodium hydride/oil dispersion and 250 ml dimethylformamide are stirred at 45° for 40 minutes. Thereafter 29.7 g 2-fluoro-nitrobenzene are added and stirring is continued at 50° for 80 hours. The solvent is evaporated in vacuo and the residue partitioned between 2 N hydrochloric acid and toluene. The acid phase is made alkaline with 2 N sodium hydroxide and extracted with methylene chloride. The organic phase is dried and evaporated in vacuo to give the heading compound, which recrystallised from ether has a m.p. 164°-166°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][CH2:2][CH2:3][NH2:4])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
1,2-Diaminoethane (7.55 mL, 113 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (28.9 g, 119 mmol) and triethylamine (24.9 mL, 179 mmol) in dichloromethane (600 mL). The solution was allowed to warm slowly to room temperature and stir for 20 hours. The solvent was removed under reduced pressure and 5% aqueous Na2CO3 (300 mL) was added. The resulting slurry was stirred vigorously at 0° C. for four hours. A yellow solid was isolated by vacuum filtration and dried under vacuum. The solid was purified by suction filter chromatography (silica gel, gradient elution from 98:2 to 93:7 dichloromethane/methanol) to provide the product N-(2-chloro-3-nitroquinolin-4-yl)ethane-1,2-diamine (16.0 g) that contained a small amount of an impurity.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH3:19])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[CH3:19][C@@H:9]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][NH:8]1
Reactant: C[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
1.68 g of (2R,4S)-2-Methyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.42 mmol) were dissolved in 40 ml dichloromethane and 19.2 ml (38.56 mmol) 2N HCl in diethylether dropwise added. After stirring at room temperature for 16 h, the solvents were evaporated, the residue was dissolved in water, the pH was adjusted to pH 9 with aqueous sodium hydroxide, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure to yield 1.05 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][N:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:32]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:24])[F:35])[N:31]=5)=[O:33])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccnc(C(F)(F)F)n1
Yield: 54.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (150 mg, 0.83 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg, 0.53 mmol), 1-hydroxybenzotriazole (72 mg, 0.53=mol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([C:10]2([OH:17])[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:3]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][O:17][C:10]32[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(c2cc(Cl)ccc2CO)CC1
Agent: Cl
Product: CN1CCC2(CC1)OCc1ccc(Cl)cc12

Procedure:
Treatment of 4-(4-chloro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine with hydrochloric acid by the method described in Example 16d provides 6-chloro-1,3-dihydro-1'-methylspiro[isobenzofuran-1,4'-piperidine].
Reaction SMILES: C(OC(N1C[C@@H](C)N2[C@H](CC3C2=NC(C)=C(CO)C=3)C1)=O)(C)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:44][C@@H:43]([CH3:45])[N:42]2[C@H:34]([CH2:35][C:36]3[C:41]2=[N:40][C:39]([CH2:46][CH3:47])=[C:38]([CH:48]=[O:49])[CH:37]=3)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+]>>[C:25]([O:29][C:30]([N:32]1[CH2:44][C@@H:43]([CH3:45])[N:42]2[C@H:34]([CH2:35][C:36]3[C:41]2=[N:40][C:39]([CH2:46][CH3:47])=[C:38]([CH2:48][OH:49])[CH:37]=3)[CH2:33]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [BH4-]
Agent: [Na+]
Product: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15 intermediate b), from (4R,9aR)-6-ethyl-7-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium borohydride.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:38][C:39](=[O:43])[C@@H:40](O)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:31]([O:38][C:39](=[O:43])[C@H:40]([O:28][C:27]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=1)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(CN(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) and (S)-benzyl-2-hydroxypropanoate (21 μL, 0.125 mmol, 1.1 eq, Aldrich, Milwaukee, Wis., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg, 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h, the mixture was extracted between saturated sodium bicarbonate and EtOAc, dried (Na2SO4), concentrated in vacuo, and purified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane). The isolated material was further purified via reversed phase semi-preparative HPLC to give 12 mg of benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was stirred in the presence of 10 mg of 10% Pd/C under a hydrogen atmosphere in EtOH. (5 mL) at room temperature for 16 h. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated in vacuo. The crude residue was purified via reversed phase semi-preparative HPLC to give 7.8 mg of (R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 35). 1HNMR (CDCl3, 400 MHz): δ 7.78 (m, 3H), 7.64(d, 1H), 7.48 (m, 2H), 7.25 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H), 4.87 (m, 1H), 4.04 (s, 2H), 2.53 (s, 3H), 1.32 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=3.48 min.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OC(CO)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)OC(CO)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirred mixture of the title compound from Step 1 above (0 30 g, 1.66 mmol) and Et3N (0.70 g, 6.9 mmol) in CH2Cl2 (30 mL) The reaction was stirred at room temperature for 15 h More acetic anhydride (0.10 g, 1.0 mmol) was added and the mixture was stirred for a further 5 h at room temperature. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/isohexane (1.3 to 2:3) as eluent to give 170 mg (46%) of the title product as an oil.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([OH:49])=[O:48].C(N(CC)CC)C>C(OCC)(=O)C>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([OH:49])=[O:48])=[O:5]
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cbz-D-hPro-OH (9.5 g, 36 mmol) was dissolved in ethyl acetate (100 mL) and the solution cooled to 0° C. Added to the solution was 2,4,5-trichlorophenol (7.1 g, 36 mmol) and 1,3-dicyclohexylcarbodiimide (7.4 g, 36 mmol). The reaction was stirred for 1 hour at 0° C. and 1 hour at room temperature. The precipitate was filtered and the filtrate concentrated in vacuo to an oil. The oil was dissolved in pyridine (100 mL), Pro-OH (4.2 g, 36 mmol), and triethylamine (5.0 mL, 36 mmol) were added. The reaction was stirred at room temperature (24 hours). The reaction solvent was removed in vacuo to an oil. The residue was dissolved in water (100 mL), diethyl ether (50 mL) was added and the pH adjusted to 9.5 with 2N sodium hydroxide. The aqueous layer extracted twice with diethyl ether. The aqueous layer separated, the pH adjusted to 2.8 with 3N hydrochloric acid and ethyl acetate (150 mL) was added. The organic layer was separated, dried (MgSO4), and the filtrate evaporated in vacuo to an amorphous solid (11.4 g, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O)([OH:3])=[O:2]>C(O)C.[C].[Pd]>[NH2:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:1]([OH:3])=[O:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)O)c(N)c1
Yield: 65.4 %

Procedure:
A solution of methyl 4-carboxy-3-nitrobenzoate (3 g, 13.3 mM) in ethanol (20 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium-carbon (1 g) for 40 minutes. After filtration of the catalyst, the solid was recrystallised from ethanol to give methyl 3-amino-4-carboxybenzoate (1.7 g, 65%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH:30]=[CH2:31]>>[CH2:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)[CH:30]=[CH2:31]
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: C=CCC(=N)NO
Product: C=CCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-but-3-enamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.65 min; Mass spectrum (ESI+): m/z=420 [M+H]+.