Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:21])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[C:11]([O:18][CH2:19][CH3:20])[C:8]=2[C:9]=1[CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:19]([O:18][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:5](=[O:21])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=1)[CH3:20]
Reactant: CCOc1cc(OCC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: COc1ccccc1N1CCNCC1
Product: CCOc1cc(OCC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 52 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-5,7-diethoxy-4-methyl-2H-1-benzopyran-2-one (Example 37) and 1-(2-methoxyphenyl)piperazine; yield 52% of oily crude product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=3)[CH2:5][CH2:4]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 1 l capacity three-necked flask were added 4-{trans-4'-(hydroxymethyl)cyclohexyl}benzonitrile (75.6 g, 0.35 mol) and pyridine (150 ml), followed by cooling these down to 0° C., dropwise adding a pyridine solution (150 ml) of p-toluenesulfonyl chloride (70.3 g, 0.37 mol) over one hour, agitating these at room temperature for 2 hours, allowing them to stand overnight, adding water (500 ml), extracting with toluene, three times washing with water (300 ml), drying over magnesium sulfate, removing magnesium sulfate, concentrating the residue, passing it through a silica gel column using a chloroform solution, distilling off chloroform, recrystallizing from a mixed solvent of n-heptane with ethyl acetate and drying to obtain white crystals (103.5 g). The NMR spectra of this product accorded with those of the captioned compound and its M.P. was 108.1°-110.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH2:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:20][CH2:18][CH3:19])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: CCN
Product: CCNC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 28 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (280 mg, 1.03 mmol) and ethylamine using General Procedure G and was isolated in 28% yield as a white solid. HPLC Rt=10.61 min; 1H NMR (400 mHz, CDCl3) 7.44 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz, 1H), 7.21 (dd, J=2.2, 8.4 Hz, 1H), 5.4 (bs, 1H), 3.21-3.14 (m, 2H), 2.25-2.20 (m, 2H), 1.86-1.79 (m, 2H), 1.58-1.52 (m, 5H), 1.35-1.32 (m, 1H), 1.00 (at, 3H); 13C NMR (100 mHz, CDCl3) 174.3, 144.8, 132.8, 130.9, 130.7, 128.7, 126.2, 50.5, 34.8, 34.7, 25.7, 23.0, 14.8; GC-MS (SCOUT) 12.9 min, M+ 299.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@:13]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:12]=2[CH:11]=[C:10]([O:22][CH3:23])[CH:9]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 85 °C
Yield: 78.9 %

Procedure:
A 250 ml RB flask was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (1.0 g, 2.54 mmol), PdCl2(Cy2C6H4NMe2)2 (0.126 g, 0.178 mmol) and 2-fluoropyridin-3-ylboronic acid (0.538 g, 3.81 mmol). Dioxane (12.72 mL) and potassium carbonate (1M solution) (7.63 mL, 7.63 mmol) were added, and the mixture was flushed with argon and heated to 85° C. for 30 min. The mixture was cooled to RT and diluted with EtOAc. The organic layer was separated and concentrated under reduced pressure to give a yellow foam. The residue was purified by chromatography (5-50% of EtOAc/MeOH/NH4OH 90:10:1 in EtOAc) to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.82 g, 2.003 mmol, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[H-].[Na+].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:9]1([C:5]2[CH:6]=[C:7]([OH:8])[C:2]([NH:1][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncc(-c2ccccc2)cc1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cc(-c2ccccc2)cnc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g, 10.95 mmol) in THF (anhydrous, 30 mL) was added NaH (1.31 g, 32.85 mmol) slowly. The mixture was stirred under nitrogen for 20 minutes, and then trityl chloride (3.66 g, 13.14 mmol) was added. The reaction was stirred at room temperature for over night under nitrogen. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over Na2SO4. After filtration and condensation, the crude product was purified on a silica gel column eluting with EtOAc-Hexane (1:10) to provide 5-phenyl-2-(trityl-amino)-pyridin-3-ol (1.09 g, 23% yield). MS m/z 427 [M+1].
Reaction SMILES: [OH:1][CH:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4](=O)[O:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH:4]1[C:5]([CH3:8])=[C:6]([CH3:7])[C:2](=[O:1])[O:3]1
Reactant: CC1=C(C)C(O)OC1=O
Reactant: O=S(Cl)Cl
Product: CC1=C(C)C(Cl)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.6g of 2-hydroxy-3,4-dimethyl-5-oxo-2,5-dihydrofuran and 10 ml of thionyl chloride was stirred for 2 hours at room temperature. By concentrating the reaction mixture under reduced pressure, 7.5g of light-yellowish oily 2-chloro-3,4-dimethyl-5-oxo-2,5-dihydrofuran was obtained.
Reaction SMILES: [C:1]([C:6](=[NH:8])[O-])([O:3][CH2:4][CH3:5])=[O:2].[NH2:9][C:10]1[C:19]([C:20](OCC)=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(O)C>[N:9]1[C:10]2=[N:11][C:12]3[C:17]([CH:18]=[C:19]2[C:20](=[O:21])[NH:8][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)C(=N)[O-]
Reactant: CCOC(=O)c1cc2ccccc2nc1N
Solvent: CCO
Product: CCOC(=O)c1nc2nc3ccccc3cc2c(=O)[nH]1

Procedure:
The same compound is obtained by: (a) refluxing equimolar amounts of 1-carbethoxyformimidate and ethyl 2-aminoquinoline-3-carboxylate in ethanol for 3 hours. The reaction mixture is concentrated, the product collected by filtration and recrystallized from hot chloroform; or (b) refluxing equimolar amounts of 1-carbethoxyformamidine and 2-aminoquinoline-3-carboxamide in ethanol for 3-4 hours in the presence of an equimolar amount of sodium ethoxide. The reaction mixture is worked up as described in (a) above.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.CC(C)=O.Cl[CH2:25][C:26]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[O:28][N:27]=1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:25][C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)[O:28][N:27]=4)=[CH:13][CH:14]=3)[O:9][CH:8]=2)=[CH:1][CH:2]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Solvent: CC(C)=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCc3noc(-c4cccc(C(F)(F)F)c4)n3)ccc12

Procedure:
To a suspension of daidzein (2.0 g, 7.87 mmol) in acetone (80 ml) 2 N aqueous potassium hydroxide (3.94 ml, 7.87 mmol) was added, and the mixture was sonicated for a few minutes. To this mixture was added 3-chloromethyl-5-(3-trifluoromethylphenyl)-[1,2,4]oxadiazole (2.17 g, 8.26 mmol), and the reaction mixture was refluxed for 3 days. The mixture was concentrated under reduced pressure, and the residue dissolved in methanol, mixed with silica gel, and the solvent removed under reduced pressure. Purification by flash column chromatography, eluting with methylene chloride/methanol (95/5 to 90/10) provided pure 3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methoxy)chromen-4-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:31]N>C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[CH2:13][CH2:12][C:11]2[C:10](=[CH:15][NH:16][N:31]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=C1CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To crude [1-(3-tert-Butyl-phenyl)-3-dimethylaminomethylene-4-oxo-cyclohexyl]-carbamic acid tert-butyl ester (91 mg, 0.227 mmol) was added ethanol (6 mL) and hydrazine hydrate (0.010 mL, 0.32 mmol). The reaction mixture was stirred at room temperature for 12 h then placed in a freezer overnight. The reaction mixture was concentrated under reduced pressure yielding the title compound: Rf=0.35 in 5% MeOH/CH2Cl2; retention time=1.92 min, method [7]; mass spec (ESI) 392 (25), 370 (2), 315 (24), 314 (100).
Reaction SMILES: C[O:2]S(C1C=CC=CC=1)(=O)=O.[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[CH:22][C:21]=1C1C=C(C)C=CC=1S(O)(=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Mg].Cl>CO>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COS(=O)(=O)c1ccccc1
Reactant: CCc1ccc(-c2cc(C)ccc2S(=O)(=O)O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: CCc1ccc(O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-ethylphenyl-4-methylbenzenesulfonate methylbenzenesulfonate (0.26 mmol; 100 mg) under argon, in methanol (2 mL), was added magnesium (2.61 mmol; 0.63 g). The reaction was stirred at room temperature overnight. The reaction mixture was hydrolysed with HCl 1N (3 mL) and extracted with ethyl acetate (3*5 mL). Combined organic phases were washed with saturated NaHCO3 (10 mL), dried over Na2SO4, concentrated. The residue was purified with preparative TLC (dichloromethane/cyclohexane: 9/1) to yield the title compound as a yellow oil (48 mg; 0.21 mmol; 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][O:13][CH3:14].Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:12]([O:13][CH3:14])[CH3:11])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1cccc(F)c1
Reaction time: 3 h

Procedure:
To a mixture of 3-fluorobenzoyl chloride (11.0 g, 6.70 mmol) and N,O-dimethylhydroxylamine.HCl in CHCl3 (70 mL) at 0° C. was added pyridine (14 mL) over 30 min. After a period of 3 h at room temperature, the reaction mixture was treated in the usual manner to give 12.5 g of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:12]([N:15]([CH2:17][CH3:18])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[ClH:24]>>[Cl:24][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:12]([N:15]([CH2:17][CH3:18])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)CC
Reactant: Cl
Product: CCC(C(c1ccc2nc(Cl)sc2c1)n1ccnc1)N(C)CC
Reaction time: 1 h

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine (5 mg, 0.1 mmol) and 2N HCl (5 mL) was stirred at Rt for 1 h. The mixture was filtered and evaporated to afford 1-(2-chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine. MS ESI: m/z 349.2 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].[CH2:31](I)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:31]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])[CH2:14][CH2:15]2)=[CH:20]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.119 g (0.31 mmol) of 2-(2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, 0.022 g (0.52 mmol) of NaH in 60% of mineral oil and 0.058 mL (0.41 mmol) of hexyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.047 g (34% of yield) of the desired product.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][NH:25][S:26]([C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][NH:25][S:26]([C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:28])=[O:27]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Reactant: CC(C)(C)S(=O)(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)NCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (30.4 mg, 0.07 mmol) in 3 mL of dry DMF was added 2-methyl-propane-2-sulfonic acid (2-bromo-ethyl)-amide (90 mg, 0.37 mmol) and Cs2CO3 (80 mg, 0.25 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS42 as pale yellow solid (17 mg, 41% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40])C.O>C(#N)C>[CH3:25][O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Reactant: CCCc1cc(O)ccc1OCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCCc1cc(OCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC
Reaction time: 6 h
Yield: 77.9 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.10 g, 0.36 mmol) and Cs2CO3 (0.24 g, 0.72 mmol) in 2 mL acetonitrile is added (4-hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester (0.09 g, 0.38 mmol). The solution is stirred for 6 hrs and poured into water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organics are washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (20% ethyl acetate/hexanes) to afford 0.13 g (85%) desired {4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-propyl-phenoxy}-acetic acid methyl ester. This ester is hydrolyzed in the usual way using 0.14 g ester and 3 eq. 1M LiOH in 3 mL 3:2:1 THF:MeOH:H2O to afford 0.16 g (95%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.Cl[S:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:34])=[O:33].O>ClCCl>[C:38]([O:37][C:36]([NH:35][S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:34])=[O:33])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(Cc1cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl N-(3-aminobenzyl)-N-(trifluoroacetyl)glycinate (1.95 g) and triethylamine (0.981 mL) in dichloromethane (19.5 mL) was added a solution of tert-butyl (chlorosulfonyl)carbamate (1.52 g) in dichloromethane (10.0 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and n-hexane was added thereto. The precipitated solid was collected by filtration to obtain tert-butyl N-(3-{[(tert-butoxycarbonyl)sulfamoyl]amino}benzyl)-N-(trifluoroacetyl)glycinate (2.19 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][CH:25]([CH2:28][C:29]([NH2:39])=[O:30])[CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
Compound 259 (0.077 g, 0.16 mmol) was suspended in DMF (1.5 mL) and 1,1′-carbonyldiimidazole (0.028 g, 0.17 mmol) was added. The reaction was stirred at 70° C. After 1 h, the suspension was cooled to 0° C. and ammonia gas was sparged therein. The tube was sealed and warmed to 70° C. After 1 h, the reaction was diluted in water (30 mL) and filtered. Purification by reversed phase HPLC (10-90% acetonitrile in water with 0.1% TFA) provided compound 260 (0.025 g, 26% yield) as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 1.25-1.39 (m, 2 H) 1.70-1.84 (m, 4 H) 1.89 (dt, J=7.27, 3.58 Hz, 1 H) 2.05 (d, J=7.09 Hz, 4 H) 2.14 (br. s., 2 H) 2.27 (d, J=8.31 Hz, 2 H) 2.80 (t, J=10.88 Hz, 2 H) 3.70 (d, J=12.23 Hz, 2 H) 5.52 (quin, J=9.05 Hz, 1 H) 6.80 (br. s., 1 H) 7.31 (br. s., 1 H) 7.74 (br. s., 1 H) 7.98 (br. s., 1 H) 8.05 (br. s., 1 H) 8.13 (d, J=3.91 Hz, 1 H) 8.21-8.28 (m, 1 H) 9.51 (s, 1 H) 11.36 (br. s., 1 H) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][C:11]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:26][CH:25]=1)([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])(=[O:9])[CH3:8].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]([NH:10][C:11]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([O:41][CH2:42][CH2:43][O:44]2)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:26][CH:25]=1)([CH2:17][OH:18])[CH2:12][OH:13])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(CCc1ccc(C2(CCCCc3ccccc3)OCCO2)cc1)(NC(C)=O)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)NC(CO)(CO)CCc1ccc(C2(CCCCc3ccccc3)OCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A solution of lithium aluminum hydride (2.0 g) in tetrahydrofuran (100 ml) was dropwise added a solution of diethyl 2-acetamido-2-{2-[4-(1,1-ethylenedioxy-5-phenylpentyl)phenyl]ethyl}malonate (14.0 g) in tetrahydrofuran (50 ml) at 3-13° C. over 30 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was dropwise added a saturated aqueous sodium sulfate solution (27 ml), and the mixture was stirred at room temperature for an hour. The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure to give a colorless transparent oily substance was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to give 2acetamido-2-{2-[4-(1,1-ethylenedioxy-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol (5.8 g) as a colorless transparent oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[NH:22][CH2:23][CH3:24].C(N(CC)CC)C.[NH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:18])[NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[NH:22][CH2:23][CH3:24]
Reactant: CC(C)(N)CO
Reactant: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)NC(C)(C)CO)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.374 g of the compound obtained in step B of EXAMPLE 241 in 5 ml of DCM is cooled to 0° C. and 0.34 ml of triethylamine and then 0.16 ml of 2-amino-2-methylpropan-1-ol and 0.364 g of BOP are added. The reaction mixture is stirred for 1 hour at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with water, with a 5% solution of potassium carbonate and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.3 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=170°-172° C.