Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>[OH-].[OH-].[Pd+2]>[OH:1][CH:2]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(O)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCC(O)C1CCNCC1
Reaction time: 12 h

Procedure:
A solution of 1,1-dimethylethyl {2-hydroxy-2-[1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate (2 g, 5.97 mmol) and Pd(OH)2 (1.2 g, 60 wt %) in ETOH (30 mL) was hydrogenated at 60 psi using a Parr Shaker. After 12 h, the solution was filtered through Celite® and concentrated affording the title compound as a yellow oil which was used directly without further purification: LCMS (ES) m/e 245 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21](Cl)[C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:10])[CH3:9].[H][H]>[Pd].CO>[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methanol (100 mL) and triethylamine (4.5 mL, 33 mmol) were added to 6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid (1.27 g, 3.76 mmol). 10% Palladium on carbon (350 mg) was added and the reaction was pressurized to 17 psi hydrogen. The reaction was agitated at room temperature for 3 hours. The reaction mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated to a yellow solid. The solid was diluted with water and the mixture was acidified to pH=4 with 1 N aqueous hydrochloric acid. The solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (960 mg, 84%) as a pale yellow solid. +ESI (M+H) 304.2; 1H NMR (400 MHz, CD3OD, δ): 9.19 (d, J=2.15 Hz, 1 H), 8.87 (d, J=2.15 Hz, 1 H), 8.01 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.27, 2.83 Hz, 1 H), 7.38 (d, J=2.73 Hz, 1 H), 4.78 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[C:7]([O:9]CC)=[O:8].C[C:14](C)(C)[C:15]([O-])([O-:17])[O-:16].C(O)(=O)CCCCC.[OH-].[Na+]>C1C2C(CCCC2)CCC1.CO>[C:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=[O:16])([OH:9])=[O:8]
Reactant: CCOC(=O)C(O)c1ccco1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC(=O)O
Solvent: C1CCC2CCCCC2C1
Product: O=C(O)Cc1ccoc1CC(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 2-(furan-2-yl)-2-hydroxyacetate (11.05 g, 64.5 mmol), trimethylorthoacetate (29.8 mL, 387 mmol) and hexanoic acid (2 mL) in decalin (195 mL) is heated at 180° C. for 12 hours. The reaction is cooled and extracted with methanol to provide a mixture of diester and decalin. This mixture is dissolved in methanol (250 mL), cooled to 0° C., treated with 2 M NaOH (150 mL) and stirred for 12 hours. The methanol is removed and the crude reaction is extracted with ether, and the basic layer is acidified with 6 N HCl and extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated to give 2,3-di(carboxymethyl)furan.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])=[C:4]([OH:28])[CH:3]=1.Cl[CH2:30]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:30][O:28][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:9]3=[O:27]
Reactant: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a stirred solution of 3-(4-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (4.3 g, 9.5 mmol), chloroiodomethane (1.8 mL, 25.3 mmol) in tetrahydrofuran (100 mL) was added cesium carbonate (9.9 g, 30.5 mmol) under Argon. The mixture was stirred at ambient temperature for 16 h, then filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was treated with diethyl ether/hexanes to afford 6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.46 g, 78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.30 (td, J=7.9, 1.5 Hz, 1H), 7.16-7.03 (m, 3H), 6.69 (d, J=7.9 Hz, 1H), 6.93 (dd, J=8.2, 1.8 Hz, 1H), 6.77-6.71 (m, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.42-6.37 (m, 1H), 5.06 (d, J=16.1 Hz, 1H), 4.97 (d, J=9.4 Hz, 1H), 4.86 (d, J=16.1 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.5, 161.5, 151.8, 141.4, 131.6, 129.3, 128.0, 124.5 (d), 124.0, 114.2, 112.6 (d), 109.2 (d), 80.1, 57.5, 36.9; MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][CH:19]1[O:23][C:22](=[O:24])[CH:21]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:18][CH:19]1[O:23][CH:22]([OH:24])[CH:21]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]1
Reactant: CC1CC(Sc2ccccn2)C(=O)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1CC(Sc2ccccn2)C(O)O1
Reaction time: 7.5 h
Yield: 64.5 %

Procedure:
16.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 4.3 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolane-2-one in 100 mL of tetrahydrofuran at −78° C., and the obtained mixture was then stirred for 7.5 hours. Thereafter, 15 mL of methanol was added to the reaction mixture, and 100 mL of a saturated potassium sodium tartrate aqueous solution was then added to the mixture at room temperature. The thus obtained mixture was stirred for 30 minutes, and the water layer was then removed. The water layer was extracted with 100 mL of ethyl acetate. The organic layer was combined with the extract, and the obtained mixture was then washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), so as to obtain 2.8 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]1[CH2:24][CH3:25].[BH4-].[K+]>O>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]1[CH2:24][CH3:25]
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CCC1C(O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1

Procedure:
(1-Hydroxy-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 1, using the following substances: (1-oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (7.58 g., 0.02 mole); potassium borohydride (2.0 g.); and water (200 ml.). Follwing this procedure, there is obtained (1-hydroxy-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.C1(=O)[NH:21]C(=O)C2=CC=CC=C12.[K].O.O.NN>CN(C=O)C.CO>[NH2:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 154.6 %

Procedure:
A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and potassium phtalimide (15 g) in DMF (200 ml) was stirred at 70° C. for 5 hours. After addition of water, the mixture was extracted with methylene chloride. The extract was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals. To a suspension of the crystals in methanol (500 ml) was added hydrazine hydrate (10 ml) and the mixture was refluxed for 12 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and the solution was washed with 1N-NaOH and water. The organic layer was dried and concentrated to dryness to give crystals (14.2 g, 93%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[NH:23][C:24]2[CH:30]=[C:29]([O:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:28]=[CH:27][C:25]=2[N:26]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([O:31][S:32]([C:35]4[CH:36]=[CH:37][C:38]([NH:41][CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)=[CH:39][CH:40]=4)(=[O:33])=[O:34])=[CH:30][C:24]=3[N:23]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2[nH]1
Reactant: O=C(O)CCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A solution of 3-phenyl propionic acid (9.7 mg) in dry dimethylformamide (0.6 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (21 mg) and diisopropylethylamine (12 μl). After stirring at ambient temperature for 30 minutes, 4-cyclopentylamino-benzenesulfonic acid 2-amino-3H-benzoimidazol-5-yl ester (20 mg) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed under vacuo and the residue was purified by triggered LC/MS to give 4-cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-propionylamino)-1H-benzoimidazol-5-yl ester as an off-white solid (11 mg). Mass spectrum: 505 [M+H]+; retention time=4.59 minutes.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCCc1ccc(Cl)cc1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 52 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(4-chlorophenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(4-chlorophenyl)ethyl]isonicotinamide was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.82-8.05 (m, 1H), 8.54-8.49 (m, 2H), 8.06-8.04 (m, 2H), 7.63-7.46 (m, 4H), 7.38-7.27 (m, 4H), 3.51-3.49 (m, 2H), 2.86 (t, J=7.1 Hz, 2H); MS (ES+) m/z 380.4 (M+1), 382.3 (M+2).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=2)[N:31]=1.O>N1C=CC=CC=1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)c1nc2ccc(Cl)nn2n1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 38.8 %

Procedure:
563 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 442 mg of tert-butyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate were dissolved in 5 ml of pyridine, followed by stirring at 80° C. for 13.5 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized by the addition of ethyl acetate, collected by filtration, washed with ethyl ether and dried to yield 365 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([O:32]CC5C=CC=CC=5)=[O:31])=[CH:22]4)=[O:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([OH:32])=[O:31])=[CH:22]4)=[O:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(C(=O)O)c5ccccc54)ccc3o2)n1
Yield: 83.7 %

Procedure:
A solution of benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-carboxylate (107 mg) in tetrahydrofuran (4 ml) was hydrogenated over 10% Pd--C (22 mg) at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-carboxylic acid (74.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1.C(OCC)(=O)C.Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11]([N:28]1[CH2:27][CH:26]([CH3:25])[O:31][CH:30]([CH3:32])[CH2:29]1)=[O:12]
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)C(F)(F)C(O)(Cn2cncn2)c2ccc(F)cc2F)CC(C)O1
Yield: 8.3 %

Procedure:
In 1 ml of ethanol was dissolved 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 330 mg of 2,6-dimethylmorpholine. The resulting mixture was subjected to reaction for 2 hours under reflux. Then, the reaction mixture was introduced into a mixed solvent consisting of 20 ml of ethyl acetate and 10 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform) to obtain 10 mg of 4-[3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanoyl]-2,6-dimethylmorpholine.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][O:6][CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([NH:8][CH:4]([CH2:5][O:6][CH3:7])[C:3]([OH:19])=[O:2])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
Compound 10 (0.58 g) was dissolved in 80% aqueous methanol (3.0 mL). To this solution was added anhydrous K2CO3 (0.5 g) and the reaction mixture was stirred at room temperature (8 hours). The methanol was evaporated in vacuo and the residue suspended in water (50 mL). The aqueous suspension was washed with ethyl ether (2×25 mL) and then acidified to pH 3.0 using 5N HCl. The acidified aqueous phase was extracted with ethyl acetate (3×25 mL). The ethyl acetate extracts were combined, dried (Na2SO4), filtered, and evaporated in vacuo to obtain pure 11 as a clear viscous oil (0.52 g, 95%): Rf 0.30 (10% MeOH/CHCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: Cc1cnc(Br)cc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cnc(NN)cc1C

Procedure:
3.8 g (18.4 mmol, purity 90%) of the compound from Example 20A are initially charged in 12.5 ml of ethanol. 8.9 ml (9.2 g, 183.8 mmol) of hydrazine hydrate are added, and the mixture is reacted in a single-mode microwave oven (CEM Explorer) at 170° C. (100 Watt) for 2 h. The reaction solution is then concentrated, and the residue is taken up in ethyl acetate and washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.C(N(CC)CC)C.C1(N)CCCCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](=[O:30])[NH:44][CH:48]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:47]3)=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)O)c3ccccc23)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Carboxy-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 5 (400 mg, 0.92 mmol) was dissolved in dichloromethane (5 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (350 mg, 1.84 mmol), 1-hydroxybenzotriazole (186 mg, 1.38 mmol), triethylamine (280 mg, 0.38 mL, 2.76 mmol) and cyclohexylamine (0.14 g, 0.16 mL, 1.38 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (30 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over Na2SO4. Filtration and concentration in vacuo afforded a foam that was purified via flash column chromatography (98:2 dichloromethane:methanol) to give the title compound. Wt.: 320 mg (68%). 1H NMR (300 MHz, CDCl3) δ 8.61 (m, 1H), 8.31 (m, 1H), 8.26 (d, 1H), 7.68 (m, 2H), 7.59 (d, 1H), 5.91 (d, 1H), 4.64 (d, 1H), 4.12 (m, 1H), 3.82 (m, 2H), 3.22 (m, 1H), 2.68 (m, 2H), 2.13 (m, 2H), 1.79 (m, 2H), 1.57 (m, 6H), 1.38 (s, 9H), 1.27 (m, 4H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:24][CH3:25])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=3)[CH2:14][CH3:15])=[N:10][C:9]=2[CH:26]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:18]([CH3:23])[CH:17]=3)([CH2:24][CH3:25])[CH2:14][CH3:15])=[N:10][C:9]=2[CH:26]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Yield: 95.1 %

Procedure:
2-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzooxazole-5-carboxylic acid methyl ester (2.10 g, 5.94 mmol) and 1-bromopinacolone (1.59 g, 8.87 mmol) and K2CO3 (2.04 g, 14.8 mmol) are reacted analogous to Example 1, step G to give the title compound as a pale yellow oil (2.55 g, 95%). H-NMR (ppm, CDCl3) δ: 8.43 (1H, d, J=1.3 Hz), 8.01 (1H, dd, J=1.8, 8.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.01 (1H, d, J=2.2 Hz), 6.96 (1H, dd, J=2.2, 8.4 Hz), 6.51 (1H, d, J=8.8 Hz), 4.84 (2H, s), 3.95 (3H, s), 2.38 (2H, q, J=7.5 Hz), 2.32 (2H, q, J=7.5 Hz), 2.25 (3H, s), 1.25 (9H, s), 0.76 (6H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH:15][CH3:16]>C(O)C.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)c1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In ethanol-water (2:1) (45 ml)was dissolved 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone (4.4 g) followed by addition of 50% dimethylamine (7.2 g), and the mixture was stirred at room temperature for 15 hours. After removal of ethanol, the residue was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. This residue was washed with n-hexane and dried. White powder, 4.4 g. 1H-NMR (CDCl3) δ: 1.63(9H,s), 3.10(6H,s), 7.57(1H,s).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][C:23]([OH:27])([CH3:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>O1CCCC1.O.CO>[OH:27][C:23]1([CH3:26])[CH2:22][CH2:21][CH:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@@H](C)CC1)C1CCC(C)(O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(O)CCC(N(c2cc(-c3ccccc3)sc2C(=O)O)C(=O)[C@H]2CC[C@@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-3-[(4-Hydroxy-4-methyl-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (70.0 mg, 0.149 mmol, 1 eq) in tetrahydrofuran (1 mL), water (0.5 mL) and methanol (0.5 mL) was added lithium hydroxide (19.0 mg, 0.447 mmol, 3 eq). The resulting mixture was stirred 3 h at room temperature and was then extracted with ether (2×10 mL). Aqueous phase was separated and combined organic phases were discarded. Aqueous phase was acidified to pH 1 and extracted with dichloromethane (3×30 mL). Organic phases of dichloromethane were combined, dried over sodium sulfate and concentrated. The crude was purified by chromatography (10% methanol/dichloromethane) to give 50 mg (74%) of cis-3-[(4-Hydroxy-4-methyl-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (CDCl3, 400 MHz): 7.60 ppm (d, 2H); 7.39 ppm (m, 3H); 7.03 ppm (s, 1H); 4.51 ppm (bs, 2H); 2.00 ppm (m, 1H); 1.80-1.20 ppm (m, 15H); 1.12 ppm (s, 3H); 0.71 ppm (d, 3H); 0.60 ppm (m, 2H).