Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:12]1)[CH2:10][C:9]2=[O:26].[OH-].[Na+]>>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:26])[C:8]4[C:23](=[CH:24][CH:25]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:27])=[O:2])[CH:7]=4)[O:22]3)[CH2:12]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2

Procedure:
(±)-(E)-3-[1′-Cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (260 mg, 0.704 mmol) was treated with 1 M NaOH according to the procedure described in Example 16 STEP B to give (±)-(E)-3-[1′-cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid. The acid was treated with NH2OTHP according to the procedure described in Example 16, Step C, giving (±)-(E)-3-[1′-cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Removal of the THP protecting group following the procedure described in Example 16, Step C, gave (±)-(E)-3-[1-cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide hydrochloride as pale brown solid (109 mg, 38% over three steps).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[N:6]=[N:7][NH:8][N:9]=1.[Cl:12][C:13]1[C:14]([N:19]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([CH:28]3[CH2:30][O:29]3)=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.O>O1CCCC1.C(O)(=O)C>[Cl:12][C:13]1[C:14]([N:19]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]([CH:28]([OH:29])[CH2:30][N:7]3[N:8]=[N:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]3)=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1nn[nH]n1
Reactant: COC(=O)c1cc(C2CO2)nn1-c1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
51.5 mg (2.14 mmol) of sodium hydride were initially charged in 15 ml of tetrahydrofuran, and a solution of 1380 mg (2.32 mmol) of a 25% strength solution of 5-(trifluoromethyl)-2H-tetrazole in tetrahydrofuran was added at 0° C. After 20 minutes of stirring at 0° C., 500 mg (1.78 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-(oxiran-2-yl)-1H-pyrazole-5-carboxylate were added, and the mixture was stirred at reflux temperature for 20 hours. The reaction mixture was poured into water, acidified with glacial acetic acid and then extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and then dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 286 mg (80% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-2H-tetrazol-2-yl]ethyl}-1H-pyrazole-5-carboxylate and methyl 1-(3-chloropyridin-2-yl)-3-{1-hydroxy-2-[5-(trifluoromethyl)-1H-tetrazol-1-yl]ethyl}-1H-pyrazole-5-carboxylate in a ratio of 66:34. (logP: 2.64/2.68; MH+: 418.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.73 (s, 3H), 4.31 (m, 2H), 4.48 (m, 1H), 7.10 (m, 1H), 7.54 (m, 1H), 8.05 (m, 1H), 8.50 (m, 1H).)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=O.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:22]2)=CC=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[S:22]
Reactant: Cn1c(=O)ccc2ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: Cn1c(=S)ccc2ccccc21
Yield: 181.7 %

Procedure:
Under inert atmosphere, 1 g of 1-methyl-quinolin-2-one and 25 ml of benzene were mixed together and then 1.27 g of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphos phetane (Laweseeon's reagent) were added all at once. After stirring at reflux for 1 hour, cooling, eliminating the solvent by distilling under reduced pressure and drying under a good vacuum and chromatographing, the residue was chromatographed on silica and eluted with a mixture of methylene chloride and ethyl acetate (1/1) to obtain 1 g of the product sought melting at 114° C.
Reaction SMILES: [Br-].[CH2:2]([S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:16][C:17]([F:23])([F:22])[S:18]([OH:21])(=[O:20])=[O:19]>>[F:16][C:17]([F:23])([F:22])[S:18]([O-:21])(=[O:20])=[O:19].[CH2:2]([S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C(C[S+]1CCCC1)c1ccccc1
Agent: [Br-]
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Compound (III-2) was synthesized by salt exchange of phenacyltetrahydrothiophenium bromide with trifluoromethanesulfonic acid in the same manner as above.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[OH:20])([CH3:4])([CH3:3])[CH3:2].[N:22]1([CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[CH:26]=[CH:25][N:24]=[CH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CO.C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:20][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1c(O)ccc2c1CCCC2=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A round bottom flask was charged with (2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-carbamic acid tert-butyl ester (700 mg, 2.40 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (544 mg, 2.89 mmol), triphenylphospine (759 mg, 2.89 mmol) and dry THF (14 mL). After approximately 15 nm, diethylazodicarboxylate (0.46 mL, 2.89 mmol) was added slowly. The reaction was stirred overnight and concentrated to give a yellow oil. Purification by chromatography (10-20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a white foam (0.850 g, 1.84 mmol, 77%). The structure was confirmed by NMR and mass spectrometry. MS m/z 462 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:27]=1)[CH:22]([CH3:24])[CH3:23])[C:10](=[O:19])[CH2:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C@@H:10]1[CH2:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](=[O:14])[O:19]1)[CH2:20][C@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:27]=1)[CH:22]([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of 5.51 g of (2S,5S,7S)-5-tert-butoxycarbonylamino-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-nonanoic acid in 25 mL of tetrahydrofuran is cooled to −30° C. and 10 mL of a 1.0 M solution of K-selectride in tetrahydrofuran is added dropwise within 30 minutes. The mixture is stirred for 2 hours at 30° C. and warmed to 0° C. and stirred for 16 hours. The reaction mixture is quenched with 50 mL of 1.0 M hydrochloric acid and extracted three times with 100 mL of dichloromethane. The organic layer is dried and the solvent is removed to give the title compound as a semi solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([CH2:34][OH:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([CH:34]=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12)OCc1ccccc1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of N-benzyloxycarbonyl-(L)-phenylalanyl-(L)-tryptophanol (0.60 g) and triethylamine (0.53 ml) in dimethyl sulfoxide (DMSO) (7 ml), a solution of pyridine-sulfur trioxide complex (pyridine.SO3) in DMSO (7 ml) was added drop by drop. After stirring at room temperature for 1 hour, the reaction mixture was poured over ice water and extracted with ethyl ether (60 ml×3). The ethyl ether layer was washed by sequential additions of a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline and then dried (MgSO4). After the solvent was distilled off, the residue was solidified from THF-hexane-ethyl ether to yield N-benzyloxycarbonyl-(L)-phenylalanyl-(L)-tryptophanal (0.44 g, 74%) as a colorless powder.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[CH:13]=[C:12]([CH2:14][NH2:15])[N:11]=[CH:10]1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:12]3[N:11]=[CH:10][N:9]([CH3:8])[CH:13]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cn1cnc(CN)c1
Agent: NCc1cocn1
Product: Cn1cnc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)c1
Yield: 52 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1-methyl-1H-imidazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-imidazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 52% yield: mp 174-176° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.01 (t, J=5.6 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.45 (s, 1H), 7.35-7.31 (m, 3H), 7.19-7.12 (m, 2H), 6.93 (s, 1H), 4.38 (s, 2H), 4.28 (d, J=5.7 Hz, 2H), 3.93 (t, J=8.1 Hz, 2H), 3.56 (s, 3H), 3.34 (t, J=8.1 Hz, 2H); MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1Cl
Reactant: NCc1ccccc1
Product: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1

Procedure:
A solution of 2-Chloro-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide (2.10 g, 0.00730 mol) in Benzylamine (5 mL, 0.04 mol) was heated at 100° C. for 5 hours. The benzylamine was evaporated under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0%→25% Ethyl Acetate:Hexane solvent gradient. 2-Benzylamino-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide isolated as a pale yellow solid (1.84 g, 70%).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]1([C:15]2[N:16]=[C:17]([CH2:26][CH2:27][C:28]([OH:30])=O)[NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:31]([N:33](CC)CC)C.Cl.CN.N12CCCN=C1CCCCC2>CN(C)C=O.O>[CH3:31][NH:33][C:28](=[O:30])[CH2:27][CH2:26][C:17]1[NH:16][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:18]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 20 h
Yield: 65.5 %

Procedure:
3.2 ml (0.024 mol) of isobutyl chloroformate are added dropwise at -5° to a solution of 7.0 g (0.024 mol) of 4,5-diphenylimidazole-2-propionic acid and 3.36 ml (0.024 mol) of triethylamine in 80 ml of dimethylformamide. After stirring at 0°-5° for 30 minutes 1.64 g (0.024 mol) of methylamine hydrochloride and 3.36 ml (0.024 mol) of triethylamine in 32 ml of dimethylformamide and 1.65 ml of water are added. The temperature is then left to rise to room temperature and the mixture is stirred for a further 20 hours. After concentration under reduced pressure the residue is boiled up in 250 ml of methanol and treated with 3.6 ml (0.024 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), whereby a clear solution results. 4.8 g of N-methyl-4.5-diphenylimidazole-2-propionamide, m.p. 195°-200° (dec.), result by cooling in an ice-bath. From the mother liquor there are obtained by concentration and treatment with water a further 2 g of the same product, m.p. 195°-200°. Total yield: 6.8 g (93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(Cl)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:31][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylate (15.5 g) in tetrahydrofuran (160 ml) and water (40 ml) is added, at room temperature, lithium hydroxide monohydrate (1.99 g). The mixture is stirred at room temperature for 1 hour, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. This gives 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylic acid (11.5 g).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(F)CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of thionyl chloride of 8.99 g (0.08 mol) was introduced at 20-25° C. into a dry 50 ml round-bottomed flask under a nitrogen atmosphere. Ethyl 3-hydroxy-2-fluoropropionate (10.0 g, 0.07 mol) were subsequently metered in in 1 h and the mixture was subsequently stirred at ambient temperature for a further 2 h. An amount of toluene of 3.98 g (0.04 mol), together with 0.286 g of pyridine (5 mol %), were introduced into a second round-bottomed flask with an Anschutz head and the mixture was heated to 80° C., The mixture from the 1st round-bottomed flask was added dropwise to the preheated solution in 1 h at 75-85° C. Solvents were distilled off under reduced pressure and the residue was subsequently finely distilled at 120° C. and 10 mbar. 4.1 g of distillate were obtained as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:15][C:16]=2[CH3:17])=[O:10])=[CH:5][CH:4]=1>C(O)C>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C(F)(F)F)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C(F)(F)F)cc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-trifluoromethylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-trifluoromethylbenzyl ester of melting point 163° C (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:41])[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39])([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:41])[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH2:39][C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:1])=[C:27]([O:28][CH3:29])[CH:26]=4)=[O:23])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(=O)OCCC(C)NC(C)C
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)Cc3ccc(OC)c(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6yl)benzoic acid and rac-3,4-dimethoxy-phenyl)-acetic acid 3-isopropylamino-butyl ester as described for example 1.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:9]([CH2:10][C:11]=1[CH3:12])[C:8](=[O:13])[C:7]([O:14][CH3:15])=[CH:6][C:5]2=[O:16].N#N.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([OH:16])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([OH:13])[C:9]=2[CH2:10][C:11]=1[CH3:12]
Reactant: COC1=CC(=O)C2CC(C)=C(C)CC2C1=O
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1cc(O)c2c(c1O)CC(C)=C(C)C2
Temperature: 25 °C

Procedure:
A solution of 6,7-dimethyl-2-methoxy-4a,5,8,8a-tetrahydronaphthalene-1,4-dione (4.0 g, 18.2 mmol) in MeOH (600 mL) was purged with a stream of N2 for 10 min with stirring at rt. With continued N2 purging, solid K2CO3 (2.51 g, 18.2 mmol, Baker) was added to the stirred solution. The solution immediately turned yellow. The reaction was allowed to stir for 30 min at rt under N2, after which it was brown. To this there was added a dilute HCl solution (10% concd HCl, 90% H2O, 200 mL) in one portion. The MeOH was removed in vacuo to give a colorless suspension. The suspension was cooled in an ice bath for 20 min. The suspended material was collected by filtration, washed with a dilute acid solution (as above, 3×20 mL) and dried in vacuo to yield a fluffy colorless solid (3.90 g, 98%, pure by 1H NMR analysis (unstable on TLC)); mp 200-°201° C.; 1H NMR (CDCl3) δ1.79 (s, 6H), 3.12 (m, 2H), 3.25 (m, 2H), 3.83 (s, 3H), 4.25 (s, 1H), 5.25 (s, 1H), 6.35 (s, 1H).
Reaction SMILES: COC(=O)[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)=[CH:10][CH:9]=1)(C)[CH3:6].[Li+].[OH-].C[C:41]([OH:43])=[O:42]>C1COCC1.CO.[Cl-].[Na+].O>[CH3:36][S:33]([C:30]([C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([C:5]([CH3:6])([CH3:4])[C:41]([OH:43])=[O:42])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)([CH3:32])[CH3:31])(=[O:35])=[O:34]
Reactant: CC(=O)O
Reactant: COC(=O)CC(C)(C)c1ccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-3-methyl-butyric acid methyl ester (1.0 eq.) from Step 1, in THF:MeOH (2:1; 0.2M) was added aqueous LiOH (2M; 5.0 eq.). The mixture was stirred for 4 h at 60° C., quenched with AcOH (20 eq.), poured in brine and extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Crystallization in Hex:Et2O:EtOAc afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.02 (t, 1H), 7.72–7.68 (m, 4H), 7.59–7.51 (m, 4H), 2.72 (s, 3H), 2.00 (s, 6H), 1.59 (s, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]([C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Oc2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Ethyl 2-bromo-5-thiazolecarboxylate(10 g), phenol (4.38 g) and potassium carbonate powder (11.7 g) are suspended in dimethylformamide (50 ml) and the suspension is stirred for 3 hours at 80° C. The reaction mixture is treated in the same manner as in Example 1 to give ethyl 2-phenoxy-5-thiazolecarboxylate (10.2 g) boiling at 127°-128° C. at 1 mmHg.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14]>ClCCl>[CH2:1]([N:8]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: CNCc1ccccc1
Agent: Br
Solvent: ClCCl
Product: CN(CC(=O)c1ccncc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-benzyl-N-methylamine (3.7 cm3) in dry dichloromethane (40 cm3), cooled to 0° C. was added with stirring, 4-bromoacetylpyridine hydrobromide (4.0 g). The reaction was allowed to warm to room temperature, then stirred for a further 18 hr. The solvent was stripped at reduced pressure, and the residue partitioned between ethyl acetate and dilute aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), evaporated, and the residue subjected to chromatography on silica gel, eluent 5% methanol in dichloromethane, to afford 4-(N-benzyl-N-methylaminoacetyl)pyridine, 1.49 g, 43%, as a yellow gum.