Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([NH:8][CH2:9][CH2:10][S:11]([CH2:12][CH3:13])=[O:23])=[N:6][CH:7]=1
Reactant: CCSCCNc1ncc(N)c(O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CCS(=O)CCNc1ncc(N)c(O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
3.2 gm of 5-amino-2-(2'-ethylmercapto-ethylamino)4-hydroxy-pyrimidine (0.015 mol) were dissolved in a mixture of 60 ml of absolute methanol and 60 ml of absolute methylene chloride. The solution was admixed with a solution of 2.89 gm (0.015 mol) of m-chloro-perbenzoic acid in 50 ml of methylene chloride at -15° C. After stirring for 8 hours at 0° C., the mixture was evaporated in vacuo to nearly dryness and was fractionated on a silicagel column with a methylene chloride/methanol mixture of at first 10:1, then 5:1. 1.42 gm (41.1%) of a uniform product were obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH2:16](I)[CH3:17].O>CN(C=O)C>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)[CH3:17]
Reactant: CCI
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OC)c2ccccc21
Temperature: 0 °C

Procedure:
In DMF (8.0 ml) was suspended sodium hydride (60% in oil, 273.9 mg, 6.846 mmol). To the resulting suspension was added methyl indole-3-carboxylate (399.8 mg, 2.282 mmol) under stirring at 0° C. The reaction mixture was stirred for 40 minutes at the same temperature. To the mixture was added ethyl iodide (0.27 ml, 3.423 mmol) at 0° C., followed by stirring at the same temperature for further 2 hours. Water was added to the reaction mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The extract was washed successively with 1N HCl and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 1-ethylindole-3-carboxylate was obtained. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.OS(O)(=O)=O>C(O)(C)(C)C>[CH:5]1([C:10]([O:12][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)C1CCCC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1CCCC1
Reaction time: 72 h
Yield: 95 %

Procedure:
Cool a metal bomb in a CO2 -acetone bath and charge with isobutylene (150 ml), cyclopentanecarboxylic acid (29.4 g, 0.26 mol), t-butanol (4 ml) and H2SO4 (1 ml). Remove the bomb from the cold-bath, seal and stir for 3 days. Cool the bomb in a CO2 -acetone bath, open to the atmosphere and evaporate isobutylene under a stream of N2 while allowing the reaction mixture to attain R.T. Add Et2O (300 ml) and wash the mixture with sat'd NaHCO3 (300 ml) and sat'd NaCl, then dry (MgSO4), filter and concentrate to obtain a colorless oil (41.5 g, 95%) which is used without further purification. 1H Nmr (CDCl3) δ2.58 (1H, m), 1.90-1.35 (8H, m), 1.39 (9H, s).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (500 mg, 1.57 mmol) in DMF (11 mL) is added TEA (0.23 mL, 1.65 mmol) and ethyl 2-chloro-2-oxoacetate (0.18 mL, 1.57 mmol) at room temperature. After stirring for 1 hour at room temperature, the reaction is quenched with H2O, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=70:30 to 50:50) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (550 mg). HPLC retention time=1.88 minutes (condition A); MS (m+1)=418.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: Oc1ccccc1Br
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Product: CN1CCC(Oc2ccccc2Br)CC1

Procedure:
The title compound was prepared from 2-bromophenol and 1-methylpiperidin-4-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: I[C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)=[O:23])=[CH:16][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:3]1[N:4]=[CH:5][N:6]=[CH:7][C:2]2=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(Nc2ncncc2I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2[nH]c3ncncc3c2c1
Reaction time: 2.5 h
Yield: 57.5 %

Procedure:
4′-[(5-Iodopyrimidin-4-yl)amino]-6-methyl-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.168 g, 0.000292 mol) was mixed with palladium acetate (0.013 g, 0.000058 mol), tri-o-tolylphosphine (0.036 g, 0.00012 mol) and sodium acetate (0.036 g, 0.00044 mol) in DMF (2.0 mL, 0.026 mol) and the mixture was heated to reflux for 4 hours. Mass spectral analysis showed ˜60% conversion. The reaction was continued for 2.5 hours at which time LCMS analysis showed ˜75% conversion. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 2:1 EtOAc/hexanes to give the product (75 mg, 57% yield). 1H NMR (CDCl3): δ □ 9.23 (s, 1H), 9.10 (brs, 1H), 9.06 (s, 1H), 8.08 (s, 1H), 7.80-8.00 (m, 5H), 7.39-7.84 (m, 5H), 2.39 (s, 3H). MS (EI) m/z=447 (M+H).
Reaction SMILES: CCCCCC.C([Li])CCC.C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)C1C=CC=CC=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.Cl.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO.[OH-].[Pd+2].[OH-].O>[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[OH:19]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: Oc1ccccc1Cc1cccc(OC(F)(F)F)c1
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 4.3 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.5 mmol) in THF (95 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of 3-trifluoromethoxybenzaldehyde (1.5 g, 7.9 mmol) in THF (32 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours and furthermore at 0° C. for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was treated by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)]. The obtained crude product was dissolved in methanol (20 mL) and a 20% palladium hydroxide catalyst (200 mg) was added and furthermore 2N—HCl (0.187 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 13 hours. Potassium carbonate (850 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.40 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Mg].C1O[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)[O:14]C1.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]2[CH2:19][CH2:20][C:15](=[O:14])[CH2:16][CH2:17]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: O=C1CCCCC12OCCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
To Grignard reagent prepared from 3,4,5-trifluorobromobenzene 100 g (474 mmol) and magnesium in 360 ml of dried tetrahydrofuran (abbreviated as THF, hereinafter) at room temperature, a THF (500 ml) solution of cyclohexanedione monoethyleneketal 74.0 g (474 mmol) was added dropwise at room temperature, and the mixture was stirred for 5 hours at room temperature. The reactant was added to one liter of 6N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid (abbreviated as PTS, hereinafter) 5 g and toluene 600 ml were added. The mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=4/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 300 ml. The catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3,4,5trifluorophenyl)cyclohexanone 52 g (228 mmol). The yield was 48.1% from 3,4,5-trifluorobromobenzene.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.C1COCC1.CC(O)=O.C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:15]([NH:14][C:12](=[O:13])[NH:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)ccc2s1
Temperature: 60 °C
Yield: 38.3 %

Procedure:
1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid (16 mg) was dissolved in EtOH (5 mL), THF (1 mL) and AcOH (0.5 mL) and 10% palladium on carbon (3 mg) was added followed by ammonium formate (78 mg). The mixture was degassed and heated at 60° C. for four days then cooled to rt. The mixture was filtered through a syringe filter and the filtrate concentrated in vacuo. The material was purified by preperative HPLC (Gilson, 40-60%, water/MeCN+0.1% formic acid). The relevant fractions were combined and freeze-dried overnight to give Compound 46 as a white solid (5.2 mg). 1H NMR ((CD3)2SO): δ 1.09 (3H, t, J=7.2 Hz), 1.13 (3H, s), 1.29 (2H, m), 2.03 (2H, br d, J=13.5 Hz), 3.17 (4H, m), 4.1 (1H, br s), 4.23 (2H, br dt, J=13.5 and 4.7 Hz), 7.43 (1H, dd, J=8.2 and 1.5 Hz), 7.6 (1H, br s), 7.83 (1H, d, J=1.5 Hz), 7.88 (1H, d, J=8.2 Hz), 8.71 (2H, s), 11.5 (1H, br s). m/z: 441 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To a solution of 6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (13.7 g, 48.7 mmol) in THF (100 mL) is added LiAlH4 (1.0 M in THF, 50 mL, 50 mmol) at 0˜5° C., the reaction mixture is stirred for 2 hr, quenched by water and 5N NaOH (0.5 mL) carefully. The resulting mixture is diluted with ethyl acetate and filtered through celite. Concentration of the filtrate gives [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (12.8 g).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[N:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:23][CH2:22][CH2:21][N:9]1[C:10]2=[N:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=[C:15]2[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1ccc2c(C3CCCCC3)c[nH]c2n1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(C3CCCCC3)cn(CCOCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a solution of 3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.0 g, 13.7 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (213 mg, 5.33 mmol) under ice-cooling, and the mixture was stirred for 15 min. After stirring, benzyl 2-bromoethyl ether (0.77 ml, 4.88 mmol) was added and the mixture was stirred at 50° C. for 1 hr. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give 1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.44 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[C:19](=[O:20])[N:9]2[CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1.O.[OH-].[Li+].Cl.ClCCl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[C:19](=[O:20])[N:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1
Reactant: CCOC(=O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 15-mL round-bottom flask ethyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (0.46 mmol) was dissolved in a mixture of THF (2 mL) and MeOH (2 mL). Lithium hydroxide monohydrate (0.93 mmol) was dissolved in water (2 mL) and added to the reaction flask dropwise. The reaction mixture was stirred at room temperature for 6 hours, and then acidified with 1N aqueous HCl. The resulting mixture containing precipitate was poured into a separatory funnel and dichloromethane added until all precipitate dissolved (200 mL). The resulting solution was washed with water (50 mL) and dried over MgSO4. Concentration yielded 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid as light-yellow precipitate. The final compound is more soluble in chloroform than dichloromethane.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26](C4C=CC=CC=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:11](CCCC)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:40])=[CH:10][C:11]=3[CH2:16][CH2:17][CH2:18][CH3:22])[N:19]=2)=[CH:25][CH:26]=1
Reactant: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.2 (d, J=1.5 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.66-7.63 (m, 3H), 7.52-7.35 (m, 4H), 6.73 (d, J=2.9 Hz, 3H), 4.20 (t, J=6.1 Hz, 2H), 3.02 (t, J=6.1 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.51-1.42 (m, 8H), 1.29 (quintet, J=7.2 Hz, 2H), 0.86 (t, J=7.1 Hz, 3H); MS (ES) m/e 514 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:4][C:3]=1[O:14][CH3:15].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:16][CH:11]([CH3:12])[C:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:14][CH3:15])[CH:4]=1)=[O:13]
Reactant: [Br-]
Reactant: CCC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)C(C)Br)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.50 g, 5.49 mmol) in anhydrous THF (20 mL) was added pyridinium tribromide (1.93 g, 6.04 mmole). The reaction was stirred at room temperature for 2 hrs then neutralized with a solution of saturated aqueous NaHCO3. The mixture was extracted with EtOAc the combined organics were washed with saturated aqueous NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (10-20% EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one as an orange oil (1.09 g, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[F:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.[BH4-].[Na+].N.[Cl-].[NH4+]>C(O)C.CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][F:14])[CH:20]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(OCCCF)c1
Reactant: NCCc1c[nH]c2cc(Cl)ccc12
Agent: N
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: FCCCOc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 6-chlorotryptamine (1.4 g, 7.2 mmol), 3-(3-fluoropropoxy)benzaldehyde (1.3 g, 7.2 mmol), and molecular sieves in ethanol (150 mL), and heat at 78° C. overnight. Filter the reaction mixture through a plug of celite, and treat the resulting filtrate with sodium borohydride (817 mg, 21.6 mmol) and stir overnight at room temperature. Evaporate the solvent in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 9:1 mixture of dichloromethane and 1N ammonia in methanol to give a residue. Chromatograph that residue on 10 g SCX column (wash column with methanol then elute with 1 N ammonia in methanol) and concentrate in vacuo to give a light yellow oil. Dissolve the oil in methanol and treated with a methanolic solution of ammonium chloride (112 mg, 2.1 mmol). Sonicate the resulting mixture for 10 minutes, remove the solvent in vacuo, and triturate the resulting residue with ether containing a few drops of acetonitrile to give a solid. Collect the solid by filtration to give the title compound as the hydrochloride: mp 177.8–178.9° C.; 1H NMR (400 MHz, dmso-d6): 11.15 (br s, 1H), 9.41 (br s, 2H), 7.57 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.32 (t, 1H, J=7.8 Hz), 7.26 (d, 1H, J=2.4 Hz), 7.25–7.21 (m, 1H), 7.11 (d, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.8, 2.0 Hz), 6.97 (dd, 1H, J=8.0, 2.0 Hz), 4.60 (dt, 2H, J=47.6, 6.0 Hz), 4.13 (br s, 2H), 4.08 (t, 2H, J=6.4 Hz), 3.10 (br s, 4H), 2.11 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS (ES+): m/e 361.3 (M+1); CHN (for C20H22ClFN2O.HCl) calcd: C 60.46, H 5.83, N 7.05; found: C 60.48, H 5.86, N 7.16.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.C(O)C.C(OCC)C.[ClH:26]>CC(C)=O>[ClH:26].[S:15]1[CH:16]=[CH:17][C:13]([CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:14]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccsc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOCC
Product: NC1=N[C@H](Cc2ccsc2)CS1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.94 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea in 9.2 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. with stirring for 3 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A greenish oil is obtained, which is taken up in 10 cm3 of acetone to give a sticky gum. 1.5 cm3 of ethanol are then added, followed by dropwise addition, with stirring, of 6 cm3 of diethyl ether. The crystals obtained are filtered off on a sinter funnel, washed with diethyl ether and then dried in an oven under vacuum (10 Pa) at a temperature in the region of 50° C. 0.5 g of (−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of gray crystals melting at 152° C. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.99 (mt: 2H); 3.26 (dd, J=11 and 5.5 Hz: 1H); 3.59 (dd, J=11 and 8 Hz: 1H); 4.54 (mt: 1H); 7.10 (dd, J=5.5 and 1 Hz 1H); 7.38 (mt: 1H); 7.54 (dd, J=5 and 3 Hz: 1H); from 9.15 to 10.55 (broad unres. mult.: 3H). (αD20=−4.3±0.5 at a concentration of 0.5% in methanol).