Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OC1(c2ccc(Oc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1

Procedure:
1-Benzyl-4-(4-phenoxy-phenyl)-piperidin-4-ol (3.47 g, 9.6 mmol, prepared in accordance with Example 7) was combined with trifluoroacetic acid (6 mL). The resulting mixture was irradiated at 130° C. in a mono-mode microwave oven for 15 min. The mixture was then concentrated under vacuum, and the obtained residue was triturated with diethyl ether (20 mL). After the solvent was removed under vacuum, the isolated product (6.6 g) was dissolved in methanol (350 mL). To this mixture was added 10% Pd/C was added (800 mg). The resulting suspension was reacted under H2 pressure (4 bar) for 5 hr at 75° C. After removing the catalyst by filtration, the filtrate was concentrated under vacuum. The obtained residue was triturated with diethyl ether (50 mL), and the precipitate was filtered and dried under vacuum. The desired product was obtained as a light yellow solid (3.26 g, 92% yield).
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[CH2:42]([O:41][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([C@@H:13]1[NH:17][C@@H:16]([CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C@:15]2([C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[NH:24][C:23]2=[O:32])[C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[F:40])=[O:12])[C:3]([OH:46])=[O:2])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester (0.13 g, 0.19 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid as a light brown solid (Yield, 0.12 g, 94%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[N:17]([CH3:44])[C:18]([CH2:31][CH2:32][NH:33]C(OCC4C=CC=CC=4)=O)=[N:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[N:17]([CH3:44])[C:18]([CH2:31][CH2:32][NH2:33])=[N:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1cc(-c2c(-c3cccc(C(F)(F)F)c3)nc(CCNC(=O)OCc3ccccc3)n2C)ccn1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Nc1cc(-c2c(-c3cccc(C(F)(F)F)c3)nc(CCN)n2C)ccn1)c1ccccc1
Reaction time: 5 h
Yield: 95 %

Procedure:
A solution of (S)-1-phenyl-N-{4-[2-(2-(benzyloxycarbonyl-amino)-ethyl)-3-methyl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyridin-2-yl}-ethylamine (0.20 g, 0.33 mmol) in absolute ethanol (10 mL) was flushed with argon before 10% palladium on activated carbon (0.07 g) was added. This reaction mixture, flushed with hydrogen gas, was vigorously stirred under one atmosphere of hydrogen for 5 hrs, then filtered and concentrated. The residue was purified by silica gel chromatography to yield 146 mg of the desired product as an oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:26][OH:27].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH:26]=[O:27]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
Pyridinium chlorochromate (PCC, 1.04 g, 4.8 mmol) was added to a flame-dried 100 mL round bottom flask followed by dry CH2Cl2 (25.0 mL) at room temperature under Argon. Alcohol 26 (0.607 g, 2.78 mmol) was dissolved in CH2Cl2 (5.0 mL) and added slowly at room temperature. The reaction was stirred for a further 12 h at room temperature before being poured into a slurry of fluoricil, MgSO4, and CH2Cl2. After stirring the suspension was filtered through celite and condensed. The resulting solid was purified by flash column chromatography (CH2Cl2) to provide 27 (0.510 g, 2.36 mmol, 85%) as white needles. The product was also purified by recrystallization in Et2O:hexanes if no starting material was present.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[C:12]([CH3:13])[C:5]=2[O:4]1.C1COCC1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC>O.CCOCC>[C:22]1([CH:32]([NH:34][C:14]([C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][CH:3]([CH2:2][OH:1])[O:4][C:5]=3[C:12]=2[CH3:13])=[O:16])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC(C)c2cccc3ccccc23)ccc2c1OC(CO)CO2

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (2.00 g, 8.92 mmol), THF (45 mL), (R)-(+)-1-(1-naphthyl)ethylamine (2.23 mL, 8.92 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.53 g, 9.81 mmol). This mixture was stirred at room temperature for 36 hours. A few drops of water were added and the mixture stirred for 5 minutes. The reaction was diluted with ether and washed once with 1N HCl, once with saturated sodium bicarbonate (aq), once again with 1N HCl, dried over magnesium sulfate, filtered and evaporated to provide 3-hydroxymethyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide. Crystals of acceptable purity for x-ray crystallography were obtained by subliming the material twice under vacuum at 60° C. This x-ray analysis established the regiochemistry and the absolute stereochemistry of the compounds as shown, since the configuration of the naphthylethylamine stereocenter is known and not subject to racemization under the conditions of synthesis. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 1.71 (d, 3H), 2.22 (s, 3H), 3.80 (m, 2H), 4.06 (m, 1H), 4.23 (m, 2R), 4.32 (m, 1H), 6.09 (m, 1H), 6.65 (d, 1H), 6.87 (d, 1H), 7.55 (m, 3H), 7.69 (m, 2H), 7.83 (d, 1H), 7.94 (d, 1H), 8.35 (d, 1H); TLC Rf=0.12 (1:1 ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1.C(N(C(C)C)CC)(C)C>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.5 mL (13.1 mmol) of 3-methoxyphenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined, and reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is purified by chromatography using HPLC through an RP column (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:41])[NH2:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@:15]([CH3:21])(O)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.C[OH:44]>CCOC(C)=O>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@H:15]([CH2:21][OH:44])[C:16]([CH3:18])([CH3:17])[CH3:19])=[O:13])[CH2:10][C:9]([OH:8])=[O:42])[CH:23]=3)=[CH:28][CH:29]=2)=[CH:38][CH:37]=1)(=[O:41])[NH2:40]
Reactant: CO
Reactant: CC(C)(C)[C@](C)(O)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1
Yield: 88 %

Procedure:
According to the procedures described in Example 1(a), 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(1(S)-hydroxy-methyl-2,2-dimethyl-propyl)succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to afford in 88% yield 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid as a white powder, mp 192-4° C. 1H NMR (CD3OD): δ 7.95 (d, 2H, J=8.4 Hz), 7.72 (d, 2H, J=8.1 Hz), 7.60 (s, 4H), 7.32 (d, 1H, J=1.6 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.51 (s, 1H), 5.20 (t, 1H, J=7.5 Hz), 3.85-3.75 (m, 2H), 3.02 (dd, 1H, J=7.2, 17.0 Hz), 0.92 (s, 9H). IR (KBr): 3360, 2961, 1710, 1658, 1404, 1201, 770 cm1; HRFABMS: Calculated for C27H32N3O5 (M+H)+: 478.2342. Found: 478.2360. Anal. Calculated for C27H32N3O5 (M+H)+. 478.2342. Found: 478.2360. Anal Calculated for C27H31N3O5.0.25CH2Cl2: C, 65.62; H, 6.37; N, 8.42. Found: C, 65.86, H, 6.69; N, 8.30.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]1[CH2:11][CH:10]([C:12](OC)=[O:13])[C:9]1([CH3:17])[CH3:16]>C1COCC1>[NH2:7][CH:8]1[CH2:11][CH:10]([CH2:12][OH:13])[C:9]1([CH3:17])[CH3:16]
Reactant: COC(=O)C1CC(N)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)C(N)CC1CO
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (2.8 equiv.) in dry THF (1.7 M) was added a solution of crude methyl 3-amino-2,2-dimethylcyclobutanecarboxylate (1.0 equiv.) in dry THF (0.7 M) at 0° C. Then the mixture was stirred under vigorously at 10° C. for 0.5 h, and then heated to 35-40° C. for 12 h. The reaction was quenched by addition of water, aqueous sodium hydroxide solution (3N) slowly at 0° C., and water. The mixture was stirred at 10° C. for 20 min, filtered through celite, and washed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the crude title compound (3-amino-2,2-dimethylcyclobutyl)methanol as a racemic mixture (89.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O[NH:33][C:34](=[NH:54])[C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH:37]=[N:38][N:39]2[CH2:44][CH2:45][C:46]([CH3:53])([CH3:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C.CCOC(C)=O.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:33]=[C:34]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[CH:37]=[N:38][N:39]4[CH2:44][CH2:45][C:46]([CH3:52])([CH3:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:54]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)C(C)(C)CCn1ncc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CCn1ncc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 50 °C
Reaction time: 120 h
Yield: 70.3 %

Procedure:
5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D31) (67.7 mg, 0.314 mmol) then triethylamine (88 μl, 0.628 mmol) followed by HOBT (57.7 mg, 0.377 mmol), EDC (72.3 mg, 0.377) and ethyl 4-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylbutanoate (D114) (100 mg, 0.314 mmol) were dissolved in DMF (4 ml) at room temperature then stirred at 50° C. for 5 days. The mixture was cooled to room temperature and diluted with EtOAc. The organic phase was washed with water, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-40% EtOAc/cyclohexane] gave the title compound (110 mg, 67%) as a light yellow solid. MS (ES) C25H28ClN5O4 requires 497, found 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:26][CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:16]=1
Reactant: CCOC(=O)c1ccc(OCc2[nH]c3ccccc3c(=O)c2C)cc1OCC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(COc2ccc(C(=O)O)c(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Yield: 96.9 %

Procedure:
To ethyl 4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate (110 mg) were added ethanol (3 mL) and a 0.5M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to a pH of 7 by adding 1M hydrochloric acid under ice-cooling. The resulting solid was collected by filtration, washed with water, and dried to obtain 4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid (100 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(NC(C)C)(C)C.[I-].[Na+]>CN(C)C=O.O>[CH:1]1([CH2:7][CH2:8][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Temperature: 70 °C

Procedure:
2-Cyclohexylethyl bromide (1.9 g.) in dimethylformamide (10 ml ) was added to 4-benzamidopiperidine (2.2 g.), diisopropylamine (4 ml.) and a trace of sodium iodide in dimethylformamide (10 ml.). The mixture was heated at 70° C. for 16 hours, cooled, poured into water, and extracted with methylene chloride. The washed and dried extracts were evaporated and the solid residue was recrystallised from ethanol to give the produce (1.25 g.), m.p. 174°-5° C. (Found: C, 76.4; H, 9.5; N, 8.9. C20H30N2O requires C, 76.4; H, 9.6; N, 8.9%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][N:7]=[C:6]2[N:11]([CH2:14][C:15]3[S:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:17][C:16]=3[CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[CH:13][C:5]=12)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:44][C:45](=[O:48])[CH2:46]Br)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=2)[S:19][C:15]=1[CH2:14][N:11]1[C:6]2=[N:7][CH:8]=[C:9]([O:10][CH2:46][C:45]([OH:48])=[O:44])[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[CH:13]=[CH:12]1)[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCc1c(O)cnc2c1ccn2Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2c(CCC)c(OCC(=O)O)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
140 mg 4-Allyl-1-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3- b]pyridin-5-ol were dissolved in 10 ml dimethylformamide and 195 mg cesium carbonate and 116 mg tert.-butylbromoacetate were added. The reaction mixture was stirred at room temperature for two hours when 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was dissolved in 10 ml dichloromethane and 4 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for three hours then 100 ml toluene were added and the solvents removed under reduced pressure. The residue was dissolved in 20 ml methanol and 50 mg palladium (10% on charcoal) were added. The reaction mixture was stirred at room temperature in a hydrogen atmosphere (5 bar) for one hour. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was purified by RP-HPLC to provide 70 mg {1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-4-propyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-acetic acid as colorless lyophilisate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1)[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH:22]=O.[CH2:33]([NH2:36])[CH2:34][CH3:35].C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][NH:36][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1
Reactant: CCCN
Reactant: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCNCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
100 mg 5-[3-Methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and 12.8 mg propylamine were suspended in 3 ml methanol. 30.0 μl triethylamine were added upon the reaction mixture became a clear solution. 400 mg molecular sieves four angstrom were added and the reaction mixture stirred at room temperature for two hours. Then 8.2 mg sodium borohydride were added and the reaction mixture stirred at room temperature for thirty minutes. The reaction mixture was filtered through a celite pad. The filtrate was evaporated in vacuo and then evaporated in vacuo. The residue was purified by RP-HPLC to obtain 45.7 mg 3-{2-methyl-4-[4-propylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as its trifluoroacetate salt.
Reaction SMILES: C1(C([N:6]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=3)[CH:17]=[CH:16][N:15]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)CC1>Cl.O1CCOCC1>[CH3:27][C:26]1[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH:19]=2)=[N:22][CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(N(C(=O)OC(C)(C)C)C(=O)C2CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Yield: 55.3 %

Procedure:
Dissolve the crude product obtained in Step 3 (2.14 g, 4.7 mmol) in HCl solution in 1,4-dioxane (5 M, 10 mL). Stir the reaction at room temperature for 17 hrs. LC/MS shows reaction is complete. Remove the solvent under reduced pressure, suspend the solid in DCM and add carefully saturated NaHCO3 solution. Separate the organic layer. Extract the aqueous layer with DCM. Combine the organic layers, dry over anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the title compound (0.9 g, 54% from step 2). MS: (M+1): 352.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC[C@H]1CC[C@H](CO)CC1

Procedure:
In 10 ml of dry tetrahydrofuran was dissolved 1.05 g of N-t-butoxycarbonyl-2-(trans-4-t-butyldimethylsilyloxymethylcyclohexyl)ethylamine, and 8.48 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture were added 150 ml of ethyl acetate, and the mixture was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (2:1) as an eluting solvent to obtain 471 mg of the desired compound as a colorless crystalline solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:3][C:2]([CH3:1])([N:6]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]2)[CH3:5])[CH2:17][CH2:16]1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Product: CN1CCN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with N-methyl piperazine to provide the title compound: MS m/z 268.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[Cl:17])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[Cl:17])=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1Cl
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3Cl)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A38”; HPLC/MS: 1.39 min, [M+H]=373;