Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([CH2:27][CH3:28])([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([CH3:26])[CH:20]=3)([CH2:27][CH3:28])[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)cc(C)c2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc(C)c2o1
Yield: 71.6 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-7-methyl-benzofuran-2-carboxylic acid ethyl ester (5.55 g, 14.6 mmol) and 1-bromopinacolone (3.92 g, 21.9 mmol) and K2CO3 (6.04 g, 43.8 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (5.00 g, 72%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[F:12].[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.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]>[F:12][C:3]1[C:2]([CH:13]=[CH2:14])=[CH:11][CH:10]=[C:5]2[C:4]=1[CH2:8][O:7][C:6]2=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2c1ccc(Br)c2F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc2c(c1F)COC2=O

Procedure:
A mixture of 5-bromo-4-fluoro-2-benzofuran-1(3H)-one (5.0 g, 21.6 mmol), potassium vinyltrifluoroborate (4.4 g, 32.5 mmol) and Pd(dppf)Cl2 (500 mg) in 100 mL of TEA and 100 mL of EtOH was heated to reflux under N2 for 4 hrs and then concentrated. The resulting oil was purified by column chromatography to give 4-fluoro-5-vinyl-3H-isobenzofuran-1-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[NH:5][CH:4]([O:18][CH:19]([CH3:21])[CH3:20])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([O:18][CH:19]([CH3:20])[CH3:21])[CH2:3]1
Reactant: CC(C)OC1CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)N=C(OC(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 0.14 g (0.45 mmol) of 4,4-dimethyl-2-iso-propoxy-1,2,3,4-tetrahydro-7-[(trimethylsilyl)ethynyl]quinoline (Compound 26) in 2.5 ml of methanol was added 0.10 g (0.72 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and the resulting oil was dissolved in water and extracted with methylene chloride (2×). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil. This compound was used for the next reaction without further purification.
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)[CH2:5]1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:3][CH:2]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[OH:1])[CH2:5]1
Reactant: COc1ccc2nccc(C(O)CN3CCCC(CNC(=O)OCc4ccccc4)C3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nccc(C(O)CN3CCC[C@@H](CN)C3)c2c1

Procedure:
20% Pd(OH)2 on carbon (0.7 g) was added to a solution of benzyl {1-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-ylmethyl}carbamate (2.51 g, 5.58 mmol) in THF (35 ml), MeOH (7 ml) was added and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The reaction mixture was filtered and the filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(F)cc2)cs1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)cs1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 29 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 29%). 1H NMR (400 MHz, CDCl3) δ 9.45 (d, J=1.3 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H), 7.86-7.82 (m, 3H), 7.35 (s, 1H), 7.11-7.07 (m, 2H), 4.05-4.00 (q, J=5.7 Hz, 2H), 3.41-3.38 (m, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O2S: 463.07. found: 464.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:18])[N:3]=1.Cl.[CH3:20][O:21][CH:22]1[CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:18][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH:22]([O:21][CH3:20])[CH2:23]2)[N:3]=1
Reactant: Clc1cc(C2CCN(C3COC3)CC2)cc(Cl)n1
Reactant: COC1CNC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
A mixture of 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (450 mg, 1.57 mmol), 3-methoxyazetidine hydrochloride (963 mg, 7.83 mmol) and DIPEA (3 mL, 16.9 mmol) in DMSO (5 mL) was stirred at 100° C. for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel (30% ethyl acetate in petroleum ether) to give 2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (320 mg, 60.3% yield). LCMS (ESI) [MH]+=337.8
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:32]Br>CCO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:32][C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:30])[F:31])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][CH2:17][CH:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:19][CH2:20]1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol (699 mg, 1.49 mmol) in EtOH (10 mL) was added bromine (77 μL, 1.49 mmol) and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with a saturated aqueous sodium thiosulfate (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated and washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10 to 25% EtOAc in hexanes) to provide 2-(3-bromo-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (567 mg) as a mixture of two enantiomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CCOC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CNS(=O)(=O)c1cncc(Br)c1
Yield: 13.3 %

Procedure:
A solution of 5-bromopyridine-3-sulfonyl chloride (3.5 g, 14 mmol) and glycine ethylester (2.1 g, 20 mmol), diisopropyl ethyl amine (2.6 g, 20 mmol) in THF (70 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was separated, dried and evaporated under reduced pressure. The residue was purified using flash silica gel column chromatography using ethyl acetate/hexanes to obtain ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (600 mg, 14%); LCMS Method T: retention time 1.31 min; [M+1]=323, 325.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.Cl.[CH3:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)=[O:45]>O1CCCC1.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:2]2[N:3]=[C:4]3[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]4[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=4)[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:47]1)=[O:45]
Reactant: CNC(=O)C1CCCNC1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)C1CCCN(c2cc(=O)n3ccc(/C=C/c4nc(C(C)C)cs4)cc3n2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (157 mg, 0.501 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 ml) and anhydrous dimethylformamide (2.5 ml), added with 4-dimethylamino-pyridine (80.0 mg, 0.651 mmol) and p-toluenesulfonyl chloride (105 mg, 0.551 mmol), and stirred at 0° C. for 1.5 hours. Subsequently, the reaction mixture was added with triethylamine (698 μl, 5.01 mmol) and N3-methyl-3-piperidinecarboxamide hydrochloride (448 mg, 2.50 mmol), and then the mixture was stirred at 60° C. for 5.5 hours. The reaction mixture was concentrated, added with saturated aqueous ammonium chloride, and then extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:2→100:3, v/v) to obtain the title compound (174 mg, 79%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].Cl[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1.O>C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: COc1ccc2nccc(CCl)c2c1
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)c2c1
Yield: 34.7 %

Procedure:
0.1 g of sodium hydride (at 60%) is added to a solution of 0.65 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 40 ml of anhydrous THF, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 30 minutes. 0.47 g of 4-chloromethyl-6-methoxyquinoline dissolved in 10 ml of THF is added. The reaction medium is refluxed for 16 hours. After cooling, 100 ml of water and 75 ml of ethyl acetate are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The brown oil obtained is purified by flash chromatography (SiO2, EtOAc/cyclohexane, 50/50 by volume, as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.36 g of 5,5-dimethyl-1-(6-methoxyquinolin-4-yl-methyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C@H:4]([NH:15]C(OCC1C=CC=CC=1)=O)[CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].P(O)(O)O>CO.[Pd].CCOCC>[NH2:15][C@@H:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)C[C@@H](CNCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: OP(O)O
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](N)CNCC(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
A solution of 17.43 g of (S)-N-[4-methyl-2-[[(phenylmethoxy)carbonyl]amino]pentyl]glycine, 1,1-dimethylethyl ester in 150 ml of methanol is reduced at 25°, 50 psi using 1 g of 20% palladium on carbon as the catalyst. The filtered solution is treated with 7.84 g of phosphorous acid in 10 ml of ether and the solvent removed under reduced pressure. The residue is partitioned between ether and 10% sodium hydroxide. The aqueous phase is washed five times with ether and the combined ether washes are washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure at 25° gives 10.28 g of crude (S)-N-(2-amino-4-methylpentyl)-glycine, 1,1-dimethylethyl ester. The crude product is sufficiently pure for use in subsequent reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21](Br)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:35][CH3:36])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:41]3[CH:42]=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=3)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:35][CH3:36])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCC1(C)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCC1(C)CN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 26.5 %

Procedure:
To a degassed mixture of 70 mg 4-[6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2-ethyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester, 21 mg 4-hydroxyphenylboronic acid and 19 mg potassium carbonate in DME/water (v/v=2/1, 0.7 mL) at r.t. and under Ar-atmosphere 2 mg palladium(0) bis(tri-tert-butylphosphine) was added and the mixture was stirred at 85° C. for 75 min in a microwave reactor. To the mixture water and ethyl acetate were added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 19 mg (27%) of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=2[O:29][CH3:30])=[C:7]([CH2:31][CH2:32][CH3:33])[CH:6]=1)C>CO.[OH-].[Na+]>[CH3:30][O:29][C:22]1[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:8]1[C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][C:7]=1[CH2:31][CH2:32][CH3:33]
Reactant: CCCc1cc(C(=O)OCC)cc(CCC)c1OCCCCCCc1cccc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)O)cc(CCC)c1OCCCCCCc1cccc(OC)c1OC

Procedure:
A solution of 1.8 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid ethyl ester in 100 mL of methanol and 20 mL of 1N sodium hydroxide was stirred at reflux for 3 hours. Workup as in Example 24 gave 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid, mp 61°-65°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]=C)[O:13][C:12]1([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]=[O:27])[O:13][C:12]1([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC1(C)OC(C=O)[C@H](CC2CCCCC2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
960 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine was dissolved in 7 ml of dioxane, and 5 ml of dioxane solution containing 35 mg of osmium tetraoxide was added thereto, and reacted for 15 minutes at room temperture in the absence of light. The reaction mixture was diluted with 2.5 ml of water, and 8 ml of a solution containing 1.15 g of sodium periodide was dropwise added over a period of 40 minutes. After the completion of the addition, the mixture was stirred for 1.5 hours at room temperature. Insolubles were filtered off, and the filtrate was diluted with 100 ml of diethyl ether. The diluted filtrate was washed sequentially with a 5% sodium sulfide solution, water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 992 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-formyl-2,2-dimethyloxazolidine as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[O:9][C:8]1=[O:23].[H][H]>O1CCOCC1.CN(C)C=O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[O:9][C:8]1=[O:23]
Reactant: O=C1OC(COc2ccc([N+](=O)[O-])cc2)CN1c1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1ccc(OCC2CN(c3ccccn3)C(=O)O2)cc1
Yield: 81.2 %

Procedure:
A 0.47 g quantity of 10% palladium carbon was added to a solution of 4.64 g of 4-[3-(2-pyridyl)-2-oxooxazolidin-5-yl]methoxynitrobenzene in 50 ml of 1,4-dioxane and 150 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 2.5 hours in a stream of hydrogen under 5 atmospheric pressure. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Methanol was added to the obtained residue to collect the crystals by filtration. Thus, 3.41 g of the title compound was obtained (yield 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH:21]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:21][C:20]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=2)[CH2:10][C@H:9]1[CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of (2R,4S)-4-amino-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.7 mmol) in methanol (2 mL) is added to 3,5-bis-trifluoromethyl-benzaldehyde (340 mg, 1.4 mmol), and the reaction mixture is stirred at room temperature. After stirring for overnight, sodium borohydride (53 mg, 1.4 mmol) is added. After stirring for additional 1 hour, The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude (2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16](O)=[O:17].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH2:23])=[O:17]
Reactant: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (5.0 grams, 0.015 mole) and carbonyldiimidazole (2.74 grams, 0.017 mole) were dissolved in 35 ml of DMF. The solution was stirred for 10 minutes and ammonium hydroxide (8 ml) was then added. The reaction mixture was stirred at room temperature for 72 hours, then poured into 150 ml of ice/water. The product precipitated and was separated by filtration, dried, and recrystallized from toluene with charcoal, yielding 3.0 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxamide, mp=191°-193° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.Cl[Pd]Cl.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.[Fe+2]>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)#[N:24]
Reactant: CCOC(=O)c1cnc(Cl)cc1NCCc1cccc(F)c1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2ccccc2C#N)cc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a mixture of ethyl 6-chloro-4-(3-fluorophenethylamino)nicotinate (1.2 g, 3.7 mmol), 2-cyano-phenylboronic acid (1.1 g, 7.4 mmol) and K2CO3 (1.5 g, 11.1 mmol) in DMF (25 mL) was added PdCl2.dppf (0.2 g, 0.37 mmol). The reaction mixture was stirred at 100° C. for 4 h. LC/MS indicated the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give ethyl 6-(2-cyanophenyl)-4-(3-fluorophenethylamino)nicotinate (500 mg, 34%). LRMS (M+H+) m/z 389.0.