Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1N=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:37]OC1C=CC(N2CCC(=O)CC2)=CC=1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)[CH2:16]3)[CH2:13][CH2:14]2)=[CH:7][CH:37]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
N-[2-({(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide whereby 1-(4-methoxyphenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.82-1.89 (m, 2H), 2.17-2.21 (m, 3H), 2.43-2.46 (m, 1H), 2.68 (q, J=11.7 Hz, 2H), 3.17-3.25 (ma 1H), 3.38-3.46 (m, 2H), 3.57-3.66 (m, 4H), 3.72 (s, 3H), 4.04 (s, 2H), 4.50-4.52 (m, 1H), 6.80-6.85 (m, 2H); 6.92-6.96 (m, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.22 (s, 1H), 8.29 (s, 2H). MS m/z: 505 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1.[CH3:20][NH:21][O:22][CH3:23]>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:17]([C:13]1[CH:12]=[C:11]([Cl:10])[N:16]=[CH:15][N:14]=1)=[O:18]
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: CNOC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20.7 mL (0.120 mol) DIPEA were added at 0° C. to 10.7 g (54.4 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 5.50 g (56.4 mmol) N,O-dimethylhydroxylamine in 150 mL DCM and stirred for 1 h at 0° C. and 1 h at RT. The mixture was diluted with DCM and washed with water. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:45]([NH:48][C:49]2[S:53][N:52]=[CH:51][N:50]=2)(=[O:47])=[O:46])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:21]=[N:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25])#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:45]([NH:48][C:49]2[S:53][N:52]=[CH:51][N:50]=2)(=[O:47])=[O:46])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[C:20]1[CH:21]=[N:22][NH:23][C:24]=1[CH3:25])#[N:2]
Reactant: Cc1c(-c2cc(C(F)(F)F)ccc2Oc2ccc(S(=O)(=O)Nc3ncns3)cc2C#N)cnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]ncc1-c1cc(C(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-cyano-4-[2-(5-methyl-1-trityl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 428, 345 mg, 0.46 mmol) was dissolved in 4N HCl in 1,4-dioxane (5 ml) and stirred at room temperature for 3 hours before concentrating in vacuo. The residue obtained was purified using an ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume). The purified compound was triturated with dichloromethane (10 mL) to afford the title compound as a white solid (148 mg, 34%-isolated as the hydrochloride salt).
Reaction SMILES: [NH:1]([C:18]([O:20]C(C)(C)C)=O)[C@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CN1CCOCC1.C(OC(=O)[C@@H:41]([N:57]=[N+:58]=[N-:59])[C:42]1([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:18](=[O:20])[C@@H:41]([N:57]=[N+:58]=[N-:59])[C:42]1([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=N[C@H](C(=O)OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](N=[N+]=[N-])C1(C(=O)OCc2ccccc2)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of Boc-γMeLeu-OBzl (0.272 g, 0.81 mmol) in 30% TFA in CH2Cl2 was stirred at 0° for 1 h. The solvent was evaporated and the residue was dried under vacuum. The resulting TFA salt was dissolved in acetonitrile (20 mL). NMM (0.53 mL, 4.86 mmol) was added to the solution, followed by the addition of (S)-α-azido-1-[(phenylmethoxy)carbonyllcyclo-pentaneacetic acid (0.269 g, 0.89 mmol, described in example 7) and BOP (0.464 g, 1.05 mmol). The mixture was stirred at room temperature for 18h. The solvent was evaporated. The residue was dissolved in EtOAc (50 mL). The solution was washed with 10% aqueous HCl (2×25 mL), a sainted aqueous solution of Na2CO3 (2×25 mL) and brine (25 mL). Evaporation of the organic phase gave N-{(S)-α-azido-1-[(phenylmethoxy)-carbonyl]cyclopentaneacetyl}-2(S)-amino-4,4-dimethylpentanoic acid benzyl ester as a yellow oil (0.400 g, 96% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 n1) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105 C-3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+310.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]([Mg]Br)=[CH:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[N:7]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[C:27]([CH3:26])=[C:28]([CH3:29])[NH:14][C:9]=12)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=C(C)[Mg]Br
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ccncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)ccnc2c1C
Temperature: -20 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
(4-Fluorobenzyl)-(3-nitropyridin-4-yl)-carbamic acid tert-butyl ester (10.2 g) prepared in Step 2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 110 ml, 130.5 mmol) was added at −78° C. to the solution, which was stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, (v/v)) to give the titled compound as a pale yellow solid (3.8 g, 28.9%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3](O)=O.N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:2]([C:3]1[C:13]2[C:12](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:11]=[CH:10][CH:9]=1)=[CH2:1]
Reactant: O=C(O)CC(=O)O
Reactant: c1ccncc1
Product: C=Cc1cccc2ccccc12

Procedure:
1-Hydrox-2-naphthylaldehyde was mixed with sodium ethoxide, and ethanol was removed to obtain sodium salt of 1-hydroxy-2- naphthylaldehyde. Subsequently, benzoyl chloride was dropped to the salt to obtain 1-benzoyloxy-2-naphthol-aldehyde. 0.9 mol of malonic acid was added to 0.25 mol of 1-benzoyloxy-2-naphthol-aldehyde, and 10 ml of pyridine was added thereto and reacted at a temperature of 110° C. for 2 hours to obtain 1-benzoyloxy-2-β-carboxyl)vinylnaphthalene. 0.14 mol of the 1-benzoyloxy-2-β-carboxyl)vinylnaphthalene was dissolved in 100 ml of quinoline, and 5 g of copper powder was added thereto and reacted for further one hour at a temperature of 220° C. to obtain 1-benzoyloxy-2-vinylnaphthalane. Next, 0.1 mol of 1-benzoyloxy-2-vinylnaphthalane was polymerized in benzene in the presence of AIBN in the same manner as in Synthetic Example 1 to obtain poly(1-benzoyloxynaphthalene). The poly(1-benzoyloxyvinylnaphthalane) of an amount corresponding to 0.5 mol of the monomer was dissolved in acetone, and 1 g of aqueous 1N sodium hydroxide solution was added thereto and heated to obtain poly(vinylnaphthol) (Resin B). The obtained polymer was purified by reprecipitating it in an acetone-water-oxalic acid solution.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[C:17]([OH:19])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:2][O:3][N:4]([CH3:5])[C:17](=[O:19])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:8])=[O:9])=[CH:15][CH:14]=1)[CH2:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (1.22 g) in acetonitrile (40 mL) was added triethylamine (4.35 mL) for neutralization, and 2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-3-yl)propanoic acid (3.12 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.40 g) and 1-hydroxybenzotriazole (191 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.96 g, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:9][CH3:10])[S:6][C:7]=1[CH3:8].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:9]([C:5]1[S:6][C:7]([CH3:8])=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCc1nc(CCl)c(C)s1
Product: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-5-methyl-1,3-thiazole (3.2 g) and triethyl phosphite (6.7 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2-1:1, v/v) to give diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate as a colorless oil (4.9 g, yield 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:18])[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:42].[F-]>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:18])[CH2:16][F:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1OCc1ccccc1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CF)c1ccccc1OCc1ccccc1
Yield: 33.1 %

Procedure:
To a solution of 1-[2-(benzyloxy)phenyl]-2-bromoethanone (2.59 g, 8.5 mmol) and pyridine (1.37 mL, 17 mmol) in THF was added tetrabutylammonium hydrogen difluoride (4.78 g, 17 mmol). The reaction mixture was stirred under reflux for 22 hrs. The mixture was diluted with ether (250 mL), then washed with 1N aqueous hydrochloric acid (100 mL) and brine (100 mL), successively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate, 4:1) to give 1-[2-(benzyloxy)phenyl]-2-fluoroethanone (688 mg, yield; 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([C:17]2[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[F:25][C:10]([F:9])([F:24])[C:11]1[CH:12]=[C:13]([C:17]2[O:21][C:20]([CH:22]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Product: Oc1ccccc1N=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Using 2-Aminophenol and 5-(3-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.44 g of 2-{[5-(3-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])=[CH:9][C:8]=2[C:33]([F:36])([F:35])[F:34])=[CH:4][CH:3]=1.[CH:39]([CH:41]=[O:42])=[O:40].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:39]([OH:40])[CH:41]([OH:42])[N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]6[NH:30][N:31]=[CH:32][C:25]=56)=[CH:21][CH:22]=4)[C:14]3=[O:15])=[CH:9][C:8]=2[C:33]([F:35])([F:36])[F:34])=[CH:37][CH:38]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Reactant: O=CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1N(c2ccc(Oc3ccnc4[nH]ncc34)cc2)C(O)C(O)N1c1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
1-[4-(4-Fluorophenoxy)-3-trifluoromethyl-phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (50 mg, 0.15 mmol) was dissolved in ethanol (5 mL), and 40% glyoxal (35 μL) and a 1 N sodium hydroxide aqueous solution (30 μL) were added thereto. The resulting mixture was stirred at 70° C. for 4 hours. The reaction solution was concentrated and then purified by reverse-phase HPLC (ODS column, 0.05% TFA-containing water/acetonitrile system, 5% to 95% linear gradient) to give the target product (9 mg, 20%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1.[NH:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:25]([O:24][C:22]([N:14]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:8]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2nccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2nccs2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a solution of 4-(thiazol-2-yl)benzyl bromide (1.25 g, 4.92 mmol) obtained in Reference Example 4-(b) in N,N-dimethylformamide (16 ml) were added di-tert-butyl iminodicarboxylate (1.28 g, 5.89 mmol) and potassium carbonate (1.35 g, 9.76 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (2.05 g) substantially quantitatively as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:4]=1.NC[CH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1.O[N:31]1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.Cl.CN(C)CCCN=C=NCC>>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH2:20][NH:31][C:13](=[O:15])[CH2:12][CH2:11][C:10]#[C:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=3)[CH:29]=2)[CH:25]=[CH:26]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCC#Cc1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccc2cc[nH]c2c1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: O=C(CCC#Cc1ccc(C(F)(F)F)cc1)NCc1ccc2cc[nH]c2c1

Procedure:
In analogy to the procedure described for example 13 a], 5-(4-trifluoromethyl-phenyl)-pent-4-ynoic acid was reacted with 6-aminoethyl-1H-indole in the presence of 1-hydroxybenzotriazole, 4-ethylmorpholine and 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride to give the title compound as colorless crystals.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12].CN(C)CCCN=C=NCC.[CH3:42][C:43]1[N:44]=[C:45]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[S:46][C:47]=1[C:48](O)=[O:49]>C(OCC)(=O)C.C(OCC)C>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:48]([C:47]3[S:46][C:45]([C:51]4[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=4)=[N:44][C:43]=3[CH3:42])=[O:49])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12]
Reactant: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
(2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt (147 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (132 mg, 0.69 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (99 mg, 0.34 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 24 h. The reaction was diluted with 100 mL diethyl ether and washed with water (100 mL), 0.5 N HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid ethyl ester (146 mg, 76%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:11]=[C:10]2[OH:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(O)c2cc(Br)ccc2n1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(O)c2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 2-amino-6-bromo-quinolin-4-ol (29.4 g, 0.12 mol), acetic anhydride (36.7 g, 0.36 mol) and sulphuric acid (20 ml) in glacial acetic acid (300 ml) was refluxed for 30 min. The mixture was allowed to cool to rt and then poured into water. The precipitate was isolated by filtration and dried to afford product N-(6-bromo-4-hydroxy-quinolin-2-yl)-acetamide as a brown solid (32 g, 93%). This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5](OC1C=C(NS(C)(=O)=O)N=C(S[CH2:20][C:21]2[CH:26]=C[CH:24]=[C:23](F)[C:22]=2F)N=1)C)[CH3:2].[BH4-].[Li+]>C1COCC1>[CH3:2][CH2:1][O:3][CH2:4][CH3:5].[CH3:24][CH2:23][CH2:22][CH:21]([CH3:26])[CH3:20]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CCOCC

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(methylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of step i) (0.28 g), THF (8 mL) and 2 M lithium borohydride in THF (1.3 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase). The resulting oil was triturated with toluene, DCM, then ether/iso-hexane to give the title compound as a white solid. Yield: 0.18 g
Reaction SMILES: C1([C:6](O)=[O:7])CCCC=1.COC1C=CC(CS)=CC=1.CO[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH:30]2[C:34]([OH:36])=[O:35])=[CH:23][CH:22]=1.C1CCCCC1>N1CCCCC1.C(O)(=O)C>[CH3:6][O:7][C:23]1[CH:22]=[CH:21][CH:26]=[CH:25][C:24]=1[CH2:27][S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]([OH:36])=[O:35]
Reactant: O=C(O)C1=CCCC1
Reactant: COc1ccc(CSC2CCCC2C(=O)O)cc1
Agent: COc1ccc(CS)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: COc1ccccc1CSC1CCCC1C(=O)O
Reaction time: 12 h

Procedure:
A solution of 1-cyclopentene carboxylic acid (1.68 g., 15 mmole) and p-methoxy-α-toluenethiol (2.17 ml., 15.6 mmole) in piperidine (3.9 ml.) is flushed with argon and heated under reflux, protected by a drying tube, for 12 hours. The mixture is then partitioned between ethyl ether (100 ml.) and 1N hydrochloric acid (3×40 ml.). The organic phase is stirred with activated charcoal (about 0.5 g.), dried (MgSO4), filtered through Celite, and concentrated in vacuo to an orange-yellow oil. This oil is recrystallized successively (3 times) from cyclohexane/hexane to yield 1.75 g. of 2-[[(4-methoxyphenyl)methyl]thio]cyclopentanecarboxylic acid as a tan, granular solid; m.p. 63°-66°. TLC (silica gel, cyclohexane:acetic acid, 8:1) Rf =0.23.