Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[CH:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=COC(C)=O
Product: CC=O
Reaction time: 5.1 h

Procedure:
The material contained in the base in Example 1 was used in this experiment. Acetic anhydride containing 1 weight percent benzenesulfonic acid was fed at 20.76 mL per hour while maintaining the acetaldehyde feed at 12 mL per hour. These feed rates gave an acetaldehyde:acetic anhydride feed ratio of 1:1. After operating 5.1 hours to adjust conditions, an additional 26.7 hours of operation produced an average of 11.5 g per hour vinyl acetate, 1.75 g per hour acetaldehyde, and 5.72 g per hour acetic acid in the overhead takeoff, which was operated to remove the distillation fraction boiling below or at 89° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([Mg]Cl)=[CH2:22].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:20][C:25](=[O:27])[CH3:26])[CH:21]=[CH2:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: C=C[Mg]Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: C=CC(OC(C)=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.9 g (10 mmol) of 1-benzenesulfonyl-1H-indole-2-carbaldehyde (synthesized analogous to M. G. Saulnier, G. W. Gordon, J.Org.Chem.; 47; 5; 1982, 757–761) in 10 ml of tetrahydrofuran was added 6.5 ml of vinylmagnesium chloride 1.7 M solution in THF at −20° C. within 1 h. The temperature increased to 0° C. within 30 min and kept at this temperature for 20 min. To the suspension 1.3 ml acetic anhydride (14 mmol was added at 0° C. within 15 min. The cooling bath was removed and after stirring for 1 h at 20° C. 10 ml water was added at 10–15° C. The mixture was stirred for an additional 1 h at 20° C. The phases were separated, and the aqueous phase was extracted with 20 ml of ethyl acetate. The combined organic phases were washed with 20 ml of brine, dried on sodium sulfate and rotary evaporated (35° C., 12 mbar). The crude material was purified by liquid chromatography (eluent isohexane/ethyl acetate 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cc(F)c2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)cc2c1NC(=S)CC2

Procedure:
To a suspension of 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one (1-3, 2.00 g, 8.19 mmol) in toluene (50 mL) was added Lawesson's reagent (1.66 g, 4.10 mmol). After refluxing the reaction mixture for 2 h, the toluene was distilled off to yield the crude product, which was then purified by flash chromatography on silica gel to obtain the title compound as a yellow solid; 1H NMR (DMSO-D6, 500 MHz) δ=12.14 (s, 1H), 7.46 (dd, J=2.0 Hz, JHF=10.0 Hz, 1H), 7.34 (s, 1H), 2.94 (d, J=8.0 Hz, 2H), 2.84 (d, J=8.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[NH:26][CH:27]=[CH:28][N:29]=4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Na+].IC.[C:37](#N)C.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[N:29]([CH3:37])[CH:28]=[CH:27][N:26]=4)=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: CC#N
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4nccn4C)c4cccnc43)CC2)ccc1Cl
Reaction time: 1 h

Procedure:
To the solution of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone (50 mg, 0.11 mmol, 1 eq) in THF was added 60% sodium hydride (5.7 mg, 0.14 mmol, 1.3 eq) and stirred for 1 hr, followed by the addition of iodomethane (25.8 mg, 0.16 mmol, 1.5 eq). 2 hrs later, LCMS indicated that the major peak is the desired product preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1-methyl-1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 465.2.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:39])[CH:28]([NH:38][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:34][CH:35]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(C[C@H](N)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid benzyl ester (Bachem, 0.459 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was passed through a plug of silica gel eluting with ethyl acetate. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.2 g, 43%), mp=99-101° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[OH:34])[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CC(C)=O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:29][C:28]=3[OH:34])[N:14]=2)=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)c(O)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a stirred mixture of 14 g of 2,4-bis(4-tert-butylphenyl)-6-(2,4-dihydroxyphenyl)-1,3,5-triazine, 10.8 g of anhydrous potassium carbonate, 0.47 g of potassium iodide, and 90 mL of acetone was added 3.7 mL (4,2 g) of ethyl chloroacetate. The mixture was stirred at reflux for 3 hr, and then cooled to room temperature. The solids were removed by filtration and washed with methylene chloride. The product was crystallized from the combined filtrate, washed with cold acetone, and dried in vacuo to give 12.5 g of 2,4-bis(4-tert-butylphenyl)-6-(2-hydroxy-4-ethoxycarbonylmethoxyphenyl)-1,3,5-triazine as a near white powder. The structure was verified by 1H-NMR spectroscopy.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[S:12])([CH3:3])[CH3:2].Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([CH:15]1[S:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[N:13][C:16]1=[O:17])[CH3:20]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: CCC(Br)C(=O)O
Product: CCC1SC(Nc2ccccc2C(C)C)=NC1=O

Procedure:
Synthesis was performed from N-(2-isopropylphenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:24][C@H:25]([C:29]([O:31]CCCC)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[C:18]([O:36][CH3:37])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[C:18]([O:36][CH3:37])[CH:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCCOC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)ccc1C(=O)N[C@H](C(=O)O)C(C)C
Temperature: 50 °C
Yield: 128.3 %

Procedure:
Butyl N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valinate (0.02 g, 0.03 mmol) was suspended in THF (1 mL), MeOH (1 mL) and water (0.5 mL), and then LiOH (0.01 g, 0.35 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and acidified with 2N HCl. The resulting solid was collected by filtration and purified by HPLC (15-80% CH3CN in H2O/0.1% TFA gradient), yielding 19 mg (91%) of the title compound. LC/MS m/z 494.1 (MH+), retention time 3.47 min. 1H NMR (400 MHz, CD3OD) δ 1.06 (d, 6H), 2.32-2.39 (m, 1H), 4.10 (s, 3H), 4.60 (d, 1H), 7.05 (t, 1H), 7.35-7.58 (m, 4H), 7.60 (d, 2H), 7.80 (d, 2H), 8.05 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[I-].C([N+]1(C)[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)C>C(O)C.O>[O:31]=[C:28]1[CH2:29][CH2:30][N:1]([CH2:2][C:3]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)C1(CN)CCOCC1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CN2CCC(=O)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a refluxing mixture of tert-butyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (8.00 g, 0.0372 mol, step 2) and K2CO3 (0.51 g, 0.0372 mol) in EtOH-H2O (2:1, 240 mL) was added dropwise 1-ethyl-1-methyl-4-oxopiperidinium iodide (12.0 g, 0.0445 mol, J. Org. Chem. 1995, 60, 4324-4330) in EtOH-H2O (2:1, 150 mL), and the resulting mixture was stirred at the same temperature (reflux) for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into sat. NaHCO3 aq. (200 mL), and the mixture was extracted with CH2Cl2 (200 mL×three times). The extracts were dried over Na2SO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (3:1 to 2:1) to give 10.77 g (98%) of the title compound as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:33])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:33])[CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COC(=O)c1ccc(N)cc1C
Product: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1C

Procedure:
120 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of methyl 4-amino-2-methylbenzoate were reacted according to General Method 5A. Following aqueous work-up, the desired product was precipitated using a mixture of a little water, acetonitrile and DMF. Yield: 120 mg (69% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[F-].[CH2:13]([N+](CCCC)(CCCC)CCCC)CCC.CI>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 2,6-dichloropurine (1.10 g, 5.82 mmol) in anhydrous THF (5.0 mL) was added tetra-n-butylammonium fluoride (0.58 mL, 10.58 mmol, 1.8 eq; 1M in THF). Methyl iodide (0.40 mL, 6.42 mmol, 1.1 eq) was added, and the reaction mixture was stirred at RT under N2 for 30 minutes. The reaction mixture was then diluted with ethyl acetate (250 mL). The organic layer was washed with aqueous saturated sodium thiosulfate solution, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane) to give 2,6-dichloro-9-methyl-9H-purine (a-2) as a white solid (780 mg, 66%) followed by gradient 0 to 30% methanol in ethyl acetate to give 2,6-dichloro-7-methyl-7H-purine (a-3) as a white solid (346 mg, 29.3%). 1H NMR of 2,6-dichloro-9-methyl-9H-purine (DMSO-d6, 400 MHz) δ ppm 8.75 (s, 1H), 3.83 (s, 3H). 1H NMR of 2,6-dichloro-7-methyl-7H-purine (DMSO-d6, 400 MHz) δ ppm 8.80 (s, 1H), 4.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:25])[C:22](Cl)=[O:23].[N:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>C(OCC)C.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]2[C:21](=[O:25])[C:22]([N:32]1[CH2:33][CH2:34][N:29]([N:27]=[O:28])[CH2:30][CH2:31]1)=[O:23]
Reactant: O=NN1CCNCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2cc(C)[nH]c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)N3CCN(N=O)CC3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 3.82 g (0.02 mol) of 5,6-dimethoxy-2-methylindole and 5,80 g (0.044 mol) of potassium carbonate in 50 ml. of chloroform and 15 ml. of water is cooled to -5° C. Then 3.2 g (0.024 mol) of oxalyl chloride is added slowly, maintaining the reaction temperature at 0° C. The resulting mixture is stirred at room temperature for 10 minutes. Then 3.5 g (0.03 mol) of nitrosopiperazine is added over a 5 minute span. The reaction mixture turns red-purple and is stirred for an additional hour. To the solution is slowly added in portions 250 ml. of ethyl ether; the solution appears lighter and a tan precipitate forms. After stirring for one hour, the product is filtered, washed well with water and dried. This product is recrystallized from a DMF and water mixture to give flakes of 1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)-4-nitrosopiperazine, m.p. 233°-225° C. Analysis: Calculated for C17H20N4O5 : 56.66% C; 5.59% H; 15.55% N Found: 56.65% C; 5.61% H; 15.68% N.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
100 mg (0.25 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 46.9 mg (0.28 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 69.5 mg (52% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10](O)[C:9]2=[O:19])=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:9](=[O:19])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=c1c(O)nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,2-dihydro-3-hydroxyquinoxalin-2-one (20 g) in phosphorus oxychloride (64 ml) was refluxed for 4 hours and then poured slowly into iced water. The resulting solid was filtered off, triturated with pentane and dried giving the title compound (19.4 g) mp>300° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C.C(O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CN(c3ncccn3)CC2C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.0 g, 4.7 mmol), 2-chloropyrimidine (0.54 g, 4.7 mmol), triethylamine (2 ml, 14 mmol) and ethyl alcohol (25 ml) was maintained at reflux for 4 hours. The solution was then cooled to room temperature and concentrated to afford a solid residue that was dissolved in dichloromethane (CH2Cl2), which was washed sequentially with sat. aq. sodium bicarbonate and brine, dried (Na2SO4), filtered, and concentrated to afford 0.82 g (60%) of the product as an orange solid: 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 3.86-3.79 (m, 2H), 3.72-3.62 (m, 2H), 3.57-3.50 (m, 2H), 3.41-3.33 (m, 1H), 3.33-3.26 (m, 1H), 3.05-2.96 (m, 2H), 1.47 (s, 9H); LRMS m/z 291 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: CN(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C)c2nccn2S(=O)(=O)N(C)C)c1C
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) and triethylamine (77 μl, 0.55 mmol) in anhydrous tetrahydrofuran (4 ml), was added dimethylsulphamoyl chloride (59 μl, 0.55 mmol). The reaction mixture was stirred at 60° C., under nitrogen, for 36 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5](=[O:35])[N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1.CO.CN(C=O)C>[O:35]=[C:5]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxo-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-acetic acid ethyl ester (229 mg, 0.46 mmol) was dissolved in THF/MeOH/DMF (3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was filtered and purified by reverse-phase preparative HPLC to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (m, 1H) 1.52 (m, 1H) 1.76 (td, J=13.89, 1.52 Hz, 2H) 2.72-2.81 (m, 1H) 2.96 (td, J=12.63, 2.27 Hz, 1H) 3.16 (d, J=5.31 Hz, 1H) 3.85 (dd, J=11.37, 2.27 Hz, 1H) 4.37 (ddd, J=12.69, 1.83, 1.64 Hz, 1H) 7.03 (d, J=8.59 Hz, 1H)-7.31 (d, J=8.34 Hz, 2H) 7.60 (d, V-8.34 Hz, 2H) 7.78 (d, J=8.84 Hz, 1H) 7.98 (dd, J=8.72, 2.65 Hz, 1H) 8.55 (d, J=2.53 Hz, 1H) 8.58 (dd, J=8.59, 2.02 Hz, 1H) 8.90 (d, J=2.27 Hz, 1H) 9.91 (s, 1H); MS (M+H)+471.2.
Reaction SMILES: [C:1]([C:8]([NH2:15])(O)[CH2:9]CCCO)(OC(C)(C)C)=[O:2].[OH:16][C:17]([CH:19]([C:21]1[CH:34]=[CH:33][CH:32]=[C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:22]=1)[CH3:20])=[O:18].[ClH:35].C([O:39][CH2:40][CH3:41])(=O)C.CCCCCC>ClCCl>[NH2:15][CH:8]([CH2:9][CH2:41][CH2:40][OH:39])[CH2:1][OH:2].[ClH:35].[OH:18][C:17]([CH:19]([C:21]1[CH:34]=[CH:33][CH:32]=[C:23]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:22]=1)[CH3:20])=[O:16]
Reactant: CC(C)(C)OC(=O)C(N)(O)CCCCO
Reactant: CCOC(C)=O
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(CO)CCCO
Reaction time: 3 h

Procedure:
The Boc-amino-1,5-pentanediol-ketoprofen (1.95 mmol) obtained above was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (4 ml) was added thereto under ice-cooling, followed by stirring for 3 hours while gradually returning to room temperature. Hexane was added to the reaction solution, and the thus formed white precipitate was centrifuged. The thus obtained precipitate was dried under reduced pressure to give the titled compound (1.20 g, yield 98%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:25][C:11]1[C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[O:14][C:10]=1[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1Cl
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of afford 5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.7 g, 2.77 mmol) in CHCl3 (10 mL), NBS (0.84 g, 4.72 mmol was added portionwise at RT. The reaction mixture was then stirred for 1 h. and diluted with DCM (20 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (340 mg, 37%) as a thick syrup.