Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C2CCc3[nH]c(C(=O)O)cc32)cc1
Yield: 26.6 %

Procedure:
The title compound was synthesized from methyl 4-p-tolyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.2888 g, 1.2 mmol, 1 equiv) and sodium hydroxide (2.94 mL, 10 M, 25 equiv) according to General Procedure 7. The resulting product was purified by preparative HPLC (water with 0.1% formic acid and 1% acetonitrile/methanol; 50 mm Dynamax HPLC C-18 column; 28 mL/min; 60% to 100% methanol) to give 4-p-tolyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (37) (76.9 mg, 28%) 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.02-7.10 (m, 4H), 6.50 (s, 1H), 4.13 (t, J=7.20 Hz, 1H), 2.68-2.94 (m, 3H), 2.29 (s, 3H), 2.14-2.25 (m, 1H); LCMS m/e 240 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]1=[O:19].[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:33][O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1>CC(C)=O>[CH3:33][O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:24][C:21]2[CH:22]=[CH:23][C:3]3[C:2]([Cl:1])=[C:6]([CH2:7][CH:8]4[CH2:12][CH2:11][N:10]([CH:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:9]4=[O:19])[S:5][C:4]=3[CH:20]=2)=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1C(Cc2sc3cc(O)ccc3c2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc3c(Cl)c(CC4CCN(C5CCCCC5)C4=O)sc3c2)cc1
Temperature: 25 °C

Procedure:
Charge a vial with 3-(3-chloro-6-hydroxy-benzo[b]thiophen-2-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (175 mg, 0.481 mmol) and dissolve in acetone (0.3 M). Add NaI (72 mg, 0.481 mmol) and Cs2CO3 (1.25 g, 3.85 mmol) and stir at room temperature for 5 minutes. Add 4-bromomethyl-benzoic acid methyl ester (220 mg, 0.96 mmol) and heat to 50° C. overnight. Cool to room temperature, filter, concentrate, and purify over silica gel to afford 4-[3-chloro-2-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-benzo[b]thiophen-6-yloxymethyl]-benzoic acid methyl ester. Dissolve in ethanol (5 mL) and water (1 mL) and add potassium hydroxide (162 mg, 2.88 mmol) and heat to 50° C. overnight. Cool to room temperature filter and dry to afford the title compound (146 mg, 61%) as a white solid: Mass spectrum (apci) m/z=498.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15]([Cl:18])(Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:18][C:15]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methylpiperazine (0.65 ml) and triethylamine (1.3 ml) in toluene (25 ml) at 0° C. was added dropwise a solution of phosgene in toluene (20%, 5.1 ml) over a period of 15 min. The reaction was allowed to warm to room temperature, stirred for 3 hr, filtered and concentrated to approximately 10 ml under reduced pressure to give a solution of 1-chlorocarbonyl-4-methylpiperazine which was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (300 mg), triethylamine (1101) and 4-dimethylaminopyridine (5 mg) in dichloromethane (10 ml) at room temperature according to the method described in Example 45. Purification of the desired material was achieved by chromatography on silica (Kieselgel 60, 230-400 mesh, Merck) (35 g) eluting with dichloromethane. Appropriate fractions were combined and evaporated to dryness under vacuum to give a material (53 mg) which was further purified by high pressure liquid chromatography on a Dynamax (trade mark) column (21.2×250 mm, 5 μm, ODS-silica, Rainin) eluting at 20 ml per minute with a methanol-water 95:5 mixture. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder. Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:43]=[CH:42][C:30]([C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38]([O:40]C)=[O:39])=[O:32])=[CH:29][CH:28]=2)O1.C([O-])(O)=O.[Na+].ClCCl.[OH-].[Na+]>CCOC(C)=O.CCO.C1(C)C=CC=CC=1>[CH3:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:28]=[CH:29][C:30]([C:31]([C@@H:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]([OH:40])=[O:39])=[O:32])=[CH:42][CH:43]=4)=[CH:3][CH:4]=3)[S:10][C:11]=2[CH:17]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc2nc(Nc3ccc(I)cc3)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3)sc2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(4-iodophenyl)-6-methyl-1,3-benzothiazol-2-amine (0.28 g, 0.78 mmol) and methyl trans-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopentanecarboxylate (0.25 g, 0.71 mmol) were combined in a dry flask under argon. Toluene (15 mL), EtOH (6 mL), and saturated aqueous NaHCO3 (2 mL) were then added, and the resulting solution was degassed by bubbling a flow of argon for 30 minutes. Then [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium (II), complex with dichloromethane (1:1) (57 mg, 0.07 mmol) was added, and the resulting mixture was heated at 85° C. for 16 h. The reaction mixture was then diluted with EtOAc and filtered through a Celite® pad. The solvent was removed by rotary evaporation and the residue was brought up in MeOH. Then 1 N aqueous NaOH (2.0 mL, 2.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was suspended in water. Concentrated HCl was added to adjust the acidity to pH 1, and the suspension was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, passed through a pad of silica gel, and concentrated in vacuo. The residue was brought up in EtOAc and the precipitate was collected by filtration, washed with EtOAc, MeOH, and DCM, and dried in a vacuum oven to afford trans-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylic acid (0.24 g, 19%). LC-MS ret. time 3.57; m/z 457.3 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.86 (m, 4H), 2.00 (m, 1H), 2.17 (m, 1H), 2.37 (s, 3H), 3.22 (q, 1H), 4.08 (q, 1H), 7.14 (m, 1H), 7.51 (d, 1H), 7.61 (s, 1H), 7.80 (m, 3H), 7.89 (d, 2H), 8.05 (d, 2H), 10.58 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[N:37]1([CH:35]([C:32]2[CH:33]=[CH:34][C:29]([NH2:6])=[CH:30][CH:31]=2)[CH3:36])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(c1ccc(Br)cc1)N1CCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(c1ccc(N)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
LiHMDS (1 mL, 1 M solution in THF, 1.0 mmol) is added to a 25 mL round bottom flask, THF is removed. Toluene (4 mL) is added followed by addition of Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and P(tBu)3 (10 mg, 0.05 mmol). The mixture is degassed. 1-[1-(4-Bromo-phenyl)-ethyl]-pyrrolidine (330 mg, 1.3 mmol) in toluene (2 mL) is added to the flask. The resulting mixture is stirred at room temperature overnight. TLC is used to determine complete consumption of starting bromide, the reaction mixture is diluted with ether at this point and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is dried and concentrated. The residue is subjected to chromatography to provide the desired product 4-(1-Pyrrolidin-1-yl-ethyl)-phenylamine (60 mg, 24%). 1H NMR (300 MHz, CDCl3) ∂ 7.09-7.13(2H, m), 6.61-6.66 (2H, m), 3.47 (2H, br), 3.11 (1H, q, J=6.6 Hz), 2.52-2.58 (2H, m), 2.33-2.39 (2H, m), 1.73-1.79 (4H, m), 1.38 (3H, d, J=6.9 Hz). MS (ESI): 191 (M+1)+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[S:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:21][CH2:22][S:18][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: C1CSCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCSC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (51.4 mg, 0.195 mM), then thiazolidine (30.7 μL, 0.390 mM) was added to the solution and then the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (48.5 mg, yield: 78%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH3:8])C.[OH-].[K+].ClCCl.S(=O)(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:12]([O:11][C:9]([N:6]([CH2:7][CH3:8])[C@H:5]([C:4]([OH:23])=[O:3])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a stirred mixture of 16 g (0.05 mole) of t-butoxycarbonyl-N-ethylphenylalanine ethyl ester (prepared as in Example 11) in 200 ml of tetrahydrofuran was added 6.6 g (0.1 mole) of potassium hydroxide in 400 ml of water. After the mixture was stirred overnight, 400 ml of dichloromethane was added and the mixture acidified to pH 3 with 0.5M sodium bisulfate. The aqueous layer was separated and washed with dichloromethane, and all organic layers were recombined. This organic solution was further washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to dryness. Column chromatography on silica gel afforded 10.9 g of the analytically pure title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH2:3][CH2:2][F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(OCCF)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCCF)C1
Yield: 77.1 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-(2-fluoroethoxy)-4-oxopiperidine-1-carboxylate obtained in Example (123b) (5.4 g, 20.6 mmol), benzylamine (2.68 g, 25 mmol), sodium (triacetoxy)borohydride (7.41 g, 35 mmol) and 1,2-dichloroethane (50 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 5.6 g of the title compound as a colorless solid (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:29][C:30]([CH3:33])=[N:31][N:32]=1.O1CCOCC1>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:29][C:30]([CH3:33])=[N:31][N:32]=1
Reactant: Cc1nnc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nnc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.252 g, 0.561 mmol) in DCM (1.121 mL) and hydrochloric acid, 4M solution in 1,4-dioxane (2.80 mL, 11.21 mmol) was stirred at rt. After 24 h, the mixture was partitioned between DCM (50 mL) and water (50 mL). The acidic aq mixture was washed with DCM (30 mL×2) to remove organic impurities. The aq layer was basified to ˜pH 13 with 10N NaOH (1 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with water (100 mL×1), dried over MgSO4, filtered, and concentrated in vacuo to give 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)-quinolin-2-yl)ethanamine as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60-8.65 (1H, m), 8.24-8.31 (1H, m), 7.80-7.91 (3H, m), 7.41-7.49 (2H, m), 4.03 (1H, q, J=6.6 Hz), 2.34 (3H, s), 2.03 (2H, br. s.), 1.24 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 350.0 [M+H]+. The solid was carried on crude without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:31]([OH:35])(=O)[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[C:31](=[O:35])[CH2:32][OH:33])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: CN(CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 100 %

Procedure:
The procedure described in Example 85 was repeated using N-[3-chloro-4-(pyridiN-2-ylmethoxy)phenyl]-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 24) and glycolic acid to give the title compound in 100% yield; Mass Spectrum: 483.8 (M+/retention time 1.30 minutes).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]#[N:16].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:5]1[O:6][C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][O:17][CH2:18][CH2:19]3)=[CH:29][CH:28]=2)=[C:3]([C:15]#[N:16])[N:4]=1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N2CCOCC2)cc1
Temperature: 180 °C
Yield: 25.7 %

Procedure:
A solution of palladium acetate (0.0057 g, 0.025 mmol) and (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (0.015 g, 0.024 mmol) in DMF (7.1 mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.100 g, 0.35 mmol), 4-morpholinoaniline (0.250 g, 1.40 mmol) and potassium phosphate tribasic (0.149 g, 0.70 mmol) were added and the mixture heated in the microwave for 3 minutes at 180° C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through a MP-SH resin cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a gradient 10-100% EtOAc in hexanes to afford 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carbonitrile (0.035 g, 0.09 mmol, 26%) as an off white solid. 1H NMR (DMSO) δ 3.08 (4H, t), 3.74 (4H, t), 6.97 (2H, d), 7.24 (2H, d), 7.33 (2H, t), 7.64 (1H, m), 10.58 (1H, s). LCMS (2) Rt: 2.92 min; m/z (ES+) 383.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.O>[C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)=[CH:10]1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)n(CC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Yield: 93.9 %

Procedure:
To a solution of ethyl 4-(1-tert-butoxycarbonylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate [1.03 g, 2.88 mmol, reference example 85b] in CH2Cl2 [10 ml] and H2O [0.125 ml] is added trifluoroacetic acid [2.5 ml]. After 18 hours removed solvent in vacuo and triturated the resulting solid with methylene chloride to give 0.815 g of the product as a white solid in 93.9% yield. 1H NMR (1:1 CD3OD:CDCl3): δ 1.43 (3H, t, J=7 Hz), 4.40 (2H, q, J=7 Hz), 4.81 (2H, s), 6.73 (1H, d, J=9 Hz), 7.60 (2H, d, J=8 Hz), 7.60 (1H, s), 7.88 (1H, d, J=9.0 Hz), 8.09 (2H, d, J=8 Hz). MS (ion spray) m/z 302 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])[CH3:2].O1CCOCC1.N1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])[CH3:2]
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccc(Br)cc2F)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCNC1
Product: CCOC(=O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of [4-allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (1.02 g, 2.40 mmol) and Pd(Ph3)4 (15 mg, 1.4 mol %) in a aq 1,4-dioxane solution (10 mL, 95% 1,4-dioxane) was treated with pyrrolidine (0.45 mL, 5.39 mmol) in a dropwise manner. After stirring for 2 h at room temperature, the solution was diluted with ethyl acetate and washed with aq 10% HCl, sat's aq NaCl, dried over Na2SO4, filtered and concentrated. The resulting crude solid was recrystallized with ethyl acetate and heptane to give [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.780 g, 76%) as a white crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]1[C:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][C:19]2[CH2:20][CH:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:18]=2[CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:13][CH2:14][CH2:15][C:16]2[C:32]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][C:19]3[CH2:20][CH:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:18]=3[CH:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCCCc1cc2c(cc1OCc1ccccc1)CC(CCc1ccccc1)O2
Reactant: N#Cc1ccc(O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCc2cc3c(cc2OCc2ccccc2)CC(CCc2ccccc2)O3)cc1
Reaction time: 0.5 h

Procedure:
4-cyanophenol (1.07 gm, 9 mmoles) was added in one portion to 50% sodium hydride dispersion (435 mgs; 9 mmoles) in dimethylformamide (30 mL) under nitrogen atmosphere. After stirring for 30 minutes, a solution of 6-(3-bromopropyl)-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E88, (1 gm, 2.2 mmoles) in dimethylformamide (5 mL) was added. The mixture was stirred at room temperature for 18 hours. The mixture was poured into excess 20% citric acid solution and extracted with diethyl ether. The ether layer was backwashed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed in silica gel using 15% ethylacetate in hexane as eluent to yield 1.06 gm (95%) as an oil of 6-[3-(4-cyanophenoxy)propyl]-5-benzyloxy-2(2-phenylethyl)-2,3-dihydrobenzofuran, E22, m.p. 154°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:26]=[C:25]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:24]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]2[N:24]=[C:25]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:28]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(CBr)n2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(OCc2nc(-c3ccc(OC)cc3)cc(-c3ccc(OC)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester 4 (0.13 g, 0.66 mmol) is dissolved in dry acetonitrile (3 mL). Cesium carbonate (0.40 g, 1.2 mmol) is added, followed by 32-bromomethyl-4,6-bis-(4-methoxy-phenyl)-pyrimidine 24 from Step C above. The mixture is stirred under nitrogen at room temperature for 18 hours. The resulting suspension is filtered, the solids are washed with more acetonitrile, and the resulting clear solution is concentrated to yield crude {4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester 25 as an oil. MS calculated for C29H29N2O6 (M+H+) 500.19. found 500.1.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[CH2:6]=[C:7]=[CH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>CCOCC>[OH:14][C:9]([CH:1]=[C:2]=[CH2:3])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][C:7]#[CH:6]
Reactant: C=C=CC(=O)CCCC
Reactant: C#CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(C=C=C)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 125 mmol. of propargylmagnesium bromide in 85 ml. of ether at -20° C. is added a solution of 11.7 g. (95 mmol.) of 1,2-octadien-4-one in 30 ml. of ether during 30 minutes. After the addition, the solution is stirred at 25° C. overnight, cooled to 0° C., and treated dropwise with 18 ml. of saturated ammonium chloride solution. The mixture is filtered, and the filtrate is washed with brine, dried over magnesium sulfate, and concentrated. The product is distilled from anhydrous potassium carbonate to provide the title compound as a colorless liquid, b.p. 84°-87° C. (7 mm.).