Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30](Cl)[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][C:44]1[S:45][C:46](B2OC(C)(C)C(C)(C)O2)=[C:47]([CH3:49])[N:48]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.O>C(#N)C>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30]([C:46]5[S:45][C:44]([CH3:43])=[N:48][C:47]=5[CH3:49])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: COc1ncc(-c2sc(C)nc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 130 °C
Yield: 8.9 %

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 1, 100 mg, 0.161 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (38.6 mg, 0.161 mmol) and K2CO3 (66.9 mg, 0.484 mmol) were mixed with 1.5 mL of 4/1 dioxane/water. The mixture was evacuated and charged with nitrogen three times, then {2-[2-(amino-κN)ethyl]phenyl-κC1}(chloro)[di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine]palladium (tert-Butyl X-Phos Precatalyst) (8.3 mg, 0.016 mmol) was added. The reaction was sealed and then heated for 25 minutes at 130° C. in a microwave reactor. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 21.2×150 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL), then eluted with 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give 10 mg product. LCMS (M+H)+: 697.4. 1H NMR (CDCl3, 500 MHz): δ 8.33 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.80 (s, 2H), 7.55 (d, J=2.1 Hz, 1H), 5.71 (d, J=8.5 Hz, 1H), 5.58 (m, 0.5H) 5.47 (m, 0.5H), 4.78 (d, J=17.1 Hz, 1H), 4.54 (m, 2H), 4.37 (m, 3H), 4.06 (d, J=18.4 Hz, 1H), 4.04 (s, 3H), 2.75 (s, 3H), 2.51 (s, 3H), 0.79 (d, J=6.5 Hz, 3H). RTA IC50: 3 nM
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH:31]([OH:34])[CH2:32][CH3:33])=[CH:26][C:25]=2[CH3:35])[C:21]=1[CH2:22][CH3:23])[CH3:4].I[CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:25]([CH3:35])=[CH:26][C:27]([CH:31]([O:34][CH2:39][CH3:40])[CH2:32][CH3:33])=[CH:28][C:29]=2[CH3:30])[C:21]=1[CH2:22][CH3:23])[CH3:4]
Reactant: CCI
Reactant: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(O)CC)cc2C)c1CC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(CC)OCC)cc2C)c1CC
Reaction time: 0.08 h
Yield: 146.5 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.031 g, 0.78 mmol) was added portionwise to a solution of 1-{4-[4-(2-ethoxy-naphthalen-1-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-3,5-dimethylphenyl}-propan-1-ol (0.123 g, 0.26 mmol) in 0.5 ml anhydrous tetrahydrofuran. After stirring 5 minutes, iodoethane (0.104 ml, 1.3 mmol) was added and the resulting mixture was stirred for 16 hours at ambient temperature. A second portion of sodium hydride (0.031 g of a 60% sodium hydride mineral oil dispersion; 0.78 mmol) was added, followed by a second portion of iodoethane (0.104 ml, 1.3 mmol). After stirring at ambient temperature for 4 hours, the reaction mixture was well-mixed with methylene chloride/aqueous sodium bicarbonate (10 ml of each). The aqueous phase was then twice extracted with 10 ml portions of fresh methylene chloride. The combined organic extracts were then dried over anhydrous sodium sulfate and concentrated in vacuo to afford a 190 mg residue. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes=1:4 in volume) afforded the title compound (45 mg) as an oil.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine in 250 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After adding 7.74 ml of DMF and stirring at −75° C. for 1 hour, the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.6 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][N:3]=1.[OH-:27].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[C:5]1[C:6]([F:8])=[CH:7][C:2]([OH:27])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(-c2cnc(Cl)cc2F)c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(-c2cnc(O)cc2F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine (140 mg, 0.37 mmol), KOH (62 mg, 1.11 mmol), Pd2(dba)3 (17 mg, 5%), and XPhos (18 mg, 10%) was suspended in 1,4-dioxane (1.9 mL) and water (316 μL). After purging the reaction vial with nitrogen for 5 min, the capped vial was stirred at 100° C. for 1 h. After the mixture cooled to rt, it was treated with 1N HCl (aq) (1 mL) and EtOAc (5 mL). The biphasic mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (˜50 mL). The filtrate was washed with water (2×30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a orange solid, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridin-2-ol (LCMS (M+H)+=363). After the solid was diluted with DMF (2.4 mL), it was treated with K2CO3 (112 mg) and MeI (23 μL). After stirring at rt for 5 h, the mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 05-95% EtOAc in hexanes) to afford the desired product, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one as a tan solid (95 mg). LCMS (M+H)+=377.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>S(Cl)(Cl)=O.CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:14])=[CH:15][CH:16]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 4-(4-bromobenzoyl)benzoic acid (87 mg, 0.29 mmol; described in: Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39(14), 2053-2056) in thionyl chloride (1 mL) at 50° C. was added a few drops of N,N-dimethylformamide. The clear solution was stirred at 50° C. for 30 min. The excess of thionyl chloride was removed under reduced pressure, and by evaporation with several portions of toluene. The residue was dissolved in dichloromethane (10 mL) and a large excess of triethylamine was added until basic pH. A solution of diethylamine (23 mg, 0.31 mmol) in dichloromethane (2 mL) was added and the mixture was stirred at room temperature for 3.5 h. The red solution was partitioned between water and additional dichlorormethane. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using heptane/ethyl acetate, 70:30, affording 70 mg (68% yield) of the title compound as a colorless oil, which partly solidified upon standing in refrigerator: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2 H), 7.70-7.63 (m, 4 H), 7.49 (d, J=8.1 Hz, 2 H), 3.59-3.57 (m, 2 H), 3.27-3.25 (m, 2 H), 1.30-1.25 (m, 3 H), 1.15-1.11 (m, 3 H); 13C NMR (400 MHz, CDCl3) δ 195.4, 170.5, 141.7, 138.0, 136.3, 132.2, 132.0, 130.5, 128.3, 126.7, 43.7, 39.7, 14.7, 13.3; MS (ESP) m/z 360 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=1)([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:43][NH:44][O:45][CH3:46].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6](=[O:7])[C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([N:44]([O:45][CH3:46])[CH3:43])=[O:19])[N:16]=1)([CH3:9])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
2-(1-tert-Butoxycarbonyl-1-methyl-ethylsulfanyl)-1,3-thiazole-4-carboxylic acid (30.34 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.17 g) and 1-hydroxybenzotriazole (13.35 g) were dissolved in dimethylformamide (550 ml) under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr 30 min. Separately, N,O-dimethylhydroxylamine hydrochloride (14.63 g) was suspended in tetrahydrofuran (50 mL), 20% aqueous potassium carbonate solution (50 mL) was added to convert same to a free amine and partitioned. The organic layer was dried over sodium sulfate. The solution after removal of desiccant was added to the dimethylformamide reaction mixture above, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (500 mL) and the mixture was stirred, and extracted twice with ethyl acetate (500 mL). The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution (each 500 mL), and dried over anhydrous sodium sulfate. The desiccant was removed, the solvent was evaporated, and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate=4/1-5/5, performed twice) to give 2-[(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (32.56 g). 30.54 g of this compound was dissolved in tetrahydrofuran (400 mL), and methylmagnesium bromide (1.4 mol/L, toluene/tetrahydrofuran=75/25 solution) (68 mL) was added dropwise over 30 min under ice-cooling. After 1 hr 25 min, methyl magnesium bromide solution (5 mL) was added, and the mixture was stirred for 1 hr 10 min. The disappearance of the starting materials was confirmed by thin layer chromatography, 0.5 mol/L aqueous hydrochloric acid (200 mL) was added, the mixture was stirred and extracted with ethyl acetate (500 mL). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 200 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate=95/5-50/50, performed 3 times) to give the title compound (21.89 g).
Reaction SMILES: [CH2:1]([NH:8][S:9](Cl)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][C:18](=[NH:21])[O:19][CH3:20])([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C1COCC1>[C:13]([NH:17][C:18](=[N:21][S:9](=[O:11])(=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:19][CH3:20])([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)(Cl)NCc1ccccc1
Reactant: COC(=N)NC(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NC(=NS(=O)(=O)NCc1ccccc1)OC
Temperature: 25 °C

Procedure:
A solution of benzylsulfamoyl chloride (168 g) in anhydrous THF (300 ml) is added dropwise to a stirred solution of N-carbomethoxy-O-methylisourea (107 g) and triethylamine (90 g) in anhydrous THF (800 ml) under nitrogen at -70° C. The resulting suspension is warmed to RT, filtered and the filtrate evaporated in vacuo. The residue is partitioned between methylene chloride and 0.5N aq. HCl. The organic layer is dried, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].ClC[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: COC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Temperature: 60 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added methyl 3-chloropropanoate (32 uL, 0.366 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to afford the title compound (88.4 mg, 75%). (300 MHz, CDCl3) δ 2.50 (3H, s), 3.74 (3H, s), 4.16 (2H, s), 4.71 (2H, s), 6.91-6.97 (3H, m), 7.06 (1H, td), 7.24 (1H, s), 7.37 (1H, d), 7.42 (1H, dd), 7.97 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd), 10.35 (1H, bs). MS (ESI) m/z 483 (MH+).
Reaction SMILES: [OH-].[Na+].[OH-].[K+].C([O:7][C:8]([C:10]1([CH3:41])[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[C:30]([Cl:40])[CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])C.C(O)(=O)C>O.O1CCCC1.C(O)C>[Cl:40][C:30]1[CH:29]=[C:28]([C:26]2[O:25][N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:16][N:13]4[CH2:12][CH2:11][C:10]([CH3:41])([C:8]([OH:9])=[O:7])[CH2:15][CH2:14]4)=[CH:22][CH:21]=3)[N:27]=2)[CH:33]=[CH:32][C:31]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)C1(C)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)c(Cl)c4)n3)cc2)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)c(Cl)c4)n3)cc2)CC1
Temperature: 80 °C

Procedure:
A solution of sodium hydroxide (0.1 g, 0.0023 mol) and potassium hydroxide (85% assay, 0.13 g, 0.0020 mol) in demineralized water (2 mL) is added to a solution of 4-methyl-1-{4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid ethyl ester (0.3 g, 0.00057 mol) in tetrahydrofuran and ethanol (14 mL, 1:1). The reaction mixture is heated under reflux (80° C.) for 2 hrs. It is then concentrated under reduced pressure to give a crude residue which is dissolved in demineralized water (10 mL) and acidified to pH˜4-5 with 20% aqueous acetic acid solution. The resultant solid is filtered, dried and washed with acetone (2×10 mL). Solid is dried under vacuum to get 1-{4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}4-methyl piperidine-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[C:16]([CH:21]=[C:22]1[NH:26][CH2:25][CH2:24][NH:23]1)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:22]2[NH:23][CH2:24][CH2:25][N:26]2[C:6]=1[CH3:8])=[O:15])[CH3:2]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1c1ccco1
Yield: 65 %

Procedure:
Boiling a solution of 6.9 g of 2-furfurylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 8 hours yields 5-methyl-7-(2-furyl)-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 164° (ethanol).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=[O:9]>>[OH:9][CH:8]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: CCOC=O
Reactant: O=C1CCCCC1
Product: O=C1CCCCC1=CO

Procedure:
As in the previous example, 200 g (2.0 mol) of cyclohexanone was reacted with ethyl formate to give 140 g of 2-hydroxymethylenecyclohexanone, XXVIIb, bp 71°-74° C (0.6 mm). Forty grams (0.32 mol) of this substance was dissolved in 150 ml CH2Cl2. containing 30 g of pyridine and treated at -5° C with a solution of 64 g (0.34 mol) of p-toluenesulfonyl chloride and 16 g of pyridine in 150 ml CH2Cl2. The reaction was stirred overnight at this temperature. Work-up in the usual manner gave the enol tosylate XXVIIIb. This was not isolated but added directly to a solution of 150 g (1.0 mol) NaI in dry acetone. After stirring overnight at room temperature this was worked up in the usual manner to give (E)-2-iodomethylenecyclohexanone, XXIXb, as a red oil. Again this was not isolated but was reduced with NaBH4 in EtOH to give crystalline dl-(E)-2-iodomethylenecyclohexanol, XXXb. Recrystallization from petroleum ether gave 40 g of white needles, mp 80° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[CH2:18][CH3:19])[C:6](OCC)=[O:7])C.[BH4-].[Na+].O>CO>[Br:17][C:13]1[C:12]([CH2:18][CH3:19])=[C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(Br)cccc1C(CO)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a solution of 2-(3-bromo-2-ethyl-phenyl)-malonic acid diethyl ester (D127) (13 g, 37.88 mmol) in methanol (130 mL) was added sodium borohydride (14.33 g, 378.78 mmol), the reaction mixture was stirred for 12 hr at room temperature. Then water was added and extracted with CH2Cl2. The organic layers were separated, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-bromo-2-ethyl-phenyl)-propane-1,3-diol (D128) (8 g). MS (ES): C11H15BrO2 requires 258.0. found 223.0 (M+H+-36).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Cl[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH:12]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: NCC(O)c1ccccc1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: OC(CNC(CCN1CCOCC1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
2-Amino-1-phenylethanol (2.50 g, 18.2 mmol) and 4-(3-chloro-3-phenylpropyl)morpholine (4.37 g, 18.2 mmol) were mixed and heated to cause reaction at 110° C. for 40 minutes. The resulting mixture was cooled to room temperature, and then dissolved into chloroform (200 ml). After the solution was chilled with ice, 1N NaOH was added so that the hydrochloride was libereated. The chloroform portion was collected and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=100/1) to obtain 2.88 g of the titled compound as a yellow oil (Yield: 46.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[C:9](=[O:23])[CH:8]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[CH:3]=3)=[CH:8][C:9]2=[O:23])=[CH:16][CH:17]=1
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 mg (0.71 mmol) 4-(3-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 8.1a) in 4.0 mL of DCM is added 100 μL (1.06 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.