Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH:4]=[N:3]1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 82.9 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), pyrrolidine (148 μl, 1.79 mmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (77 mg, 82.9%) as a light brown solid. mp.: 226-8° C. MS: m/z=417.3 (M+H+).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:8]#[N:9])=[CH:3][CH:2]=1>C(#N)C>[CH:16]([N:12]([CH:13]([CH3:14])[CH3:15])[CH2:11][CH2:10][C:7]([CH2:10][CH2:11][N:12]([CH:16]([CH3:17])[CH3:18])[CH:13]([CH3:15])[CH3:14])([C:4]1[C:3]2[C:2](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:1]=[CH:6][CH:5]=1)[C:8]#[N:9])([CH3:17])[CH3:18]
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Solvent: CC#N
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1cccc2ccccc12)C(C)C

Procedure:
Substitution of an equivalent quantity of the above acetonitrile for α-[4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile called for in Example 2, Method B, affords α,α-bis[2-(diisopropylamino)ethyl]-α-(1-naphthyl)acetonitrile, as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([OH:17])[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[CH3:18][S:19](Cl)(=[O:21])=[O:20].CCN(CC)CC>>[CH3:18][S:19]([O:17][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)[CH3:16])(=[O:21])=[O:20]
Reactant: CC(C)c1noc(N2CCC(C(C)O)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1noc(N2CCC(C(C)OS(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
A solution of (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (0.39 g) in CH2CH2 (35 mL) at 0° C. was treated with methanesulfonyl chloride (0.26 mL, 3.26 mmol) and Et3N (0.69 mL, 4.89 mmol) and stirred at 0° C. for 1 h then room temperature for 15 h. The mixture was diluted with CH2CH2 (80 mL), washed with 1M NaH2PO4 (50 mL×2) and brine (35 mL), and dried over Na2SO4 and concentrated to afford crude (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.53 g, 100%) as a light brown oil. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.75-4.65 (m, 1H), 4.30-4.15 (m, 2H), 3.10-2.95 (m, 5H), 2.89 (septet, 1H, J=7.0 Hz), 1.95-1.70 (m, 3H), 1.55-1.35 (m, 5H), 1.28 (d, 6H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:22]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:23])[CH:24]=[CH:25][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCC1CC1
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-1H-Pyrrolo[2,3-b]pyridine (4, 0.68 g, 4.46 mmol, prepared as described in Example 4), 3-benzyloxy-2-cyclopropylmethoxy-benzaldehyde (130, 1.2 g, 4.25 mmol), and potassium hydroxide (0.68 g, 11 mmol) in methanol (50 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (131, 0.99 g, 54%). MS (ESI) [M+H+]+=435.21.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[C:29]1([N:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)N)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:30]4[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:2]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cn(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2cc(F)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12

Procedure:
Ethyl 2-[6-fluoro-1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (357 mg, 1.0 mmol) was dissolved in methanol (20 mL). 10% Pd/C (15 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (3.10 mmol, 1 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the title compound (600 mg). MS (ESI) m/z 223.3 [M+H]+
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][Mg]Br>C1(C)C=CC=CC=1.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]>[CH3:11][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Mg]Br
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
Into a round bottom flask the catalyst PdCl2(dppf), under an atmosphere of nitrogen, was placed with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene was added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) was added dropwise. The solution turned from orange to yellow, and was slowly heated to 60° C. and stirred for 3 hrs at 60° C. and then overnight at room temperature. The resulting dark orange reaction mixture was quenched with 1 N hydrochloric acid and adjusted to pH ˜5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (42, 202 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=134.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]3[CH2:21][O:20][CH2:19]3)[N:13]([CH3:23])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][C:30]=1[N:45]1[CH2:56][CH2:55][C:54]2[C:53]3[CH2:52][C:51]([CH3:58])(C)[CH2:50][C:49]=3[S:48][C:47]=2[C:46]1=[O:59])(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.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]>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:45]2[C:46](=[O:59])[C:47]3[S:48][C:49]4[CH2:50][CH2:51][CH2:58][CH2:52][C:53]=4[C:54]=3[CH2:55][CH2:56]2)=[CH:31][C:32]([F:44])=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]3[CH2:21][O:20][CH2:19]3)[N:13]([CH3:23])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN(Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C)C1COC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN(C)C4COC4)n(C)n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 57 %

Procedure:
A sealed tube was charged with the mixture of 5-bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 320d (150 mg, 0.39 mmol), (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b (195 mg, 0.39 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol), K3PO4.3H2O(207 mg, 0.78 mmol), and NaOAc (63 mg, 0.78 mmol) in CH3CN (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 324a as a yellow solid (150 mg, 56%). MS: [M+H]+ 675.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:25]2=[O:26])=[C:4]([CH3:17])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1-n1nc(-c2ccco2)oc1=O
Yield: 60 %

Procedure:
A mixture of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide (0.5 mmol), triethylamine (0.1 mL, 0.75 mmol), and carbonyldiimidazole (0.24 g, 1.5 mmol) was stirred at 80° C. in 2 mL of THF overnight. The crude product obtained after removal of the solvent was then subject to chromatography (silica gel, 1:9 ethyl acetate-hexanes), followed by crystallization from hexanes to provide 83 mg (0.3 mmol, yield 60%) of 3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl-3H-[1,3,4]oxadiazol-2-one as a white solid with an HPLC purity of 98.9%. LC-MS [M+H] 277.9 (C13H9ClN2O3+H, expected 277.68). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[H-].[Na+]>C(=O)(OC)OC.C1(C)C=CC=CC=1>[O:10]=[C:7]1[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9][CH:8]1[C:4]([O:3][CH3:2])=[O:11]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC2(CCC1=O)OCCO2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1,4-cyclohexanedione monoethylene ketal (1.00 g, 6.4 mmol) in dimethyl carbonate (6 mL) at room temperature was added sodium hydride (0.31 g, 7.7 mmol). The mixture was heated at 80° C. for 20 min and then diluted with dry toluene (20 mL). The mixture was stirred for an additional 3 h at 80° C., cooled to room temperature, quenched with water, and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to yield the crude product which was purified by Biotage® chromatography (silica gel, ethyl acetate in hexanes gradient 30-42%) to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:40]=[CH:39][N:16]3[C:17](=[O:38])[C:18](/[CH:32]=[CH:33]/[C:34]([O:36]C)=[O:35])=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:40]=[CH:39][N:16]3[C:17](=[O:38])[C:18](/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1c(N2CCCC(C(=O)N(C)C)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)C1CCCN(c2nc3cc(C(=O)Nc4nc(C(C)(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The methyl (E)-3-(8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-2-{3-[(dimethylamino)carbonyl]piperidino}-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-2-propenoate (63.7 mg, 0.11 mmol) obtained in (C) was dissolved in methanol (10 ml), added dropwise with 1 N aqueous sodium hydroxide (562.0 μl, 0.56 mmol), and stirred at room temperature for 1 hour. The reaction solution was further added with 1 N aqueous sodium hydroxide (5.62 ml, 5.62 mmol), stirred at room temperature for 2 hours, further added with 1 N aqueous sodium hydroxide (2.81 ml, 2.81 mmol), and stirred at room temperature for 3 hours. The reaction solution was adjusted to about pH 2 with 1 N hydrochloric acid aqueous solution and extracted with chloroform/methanol (10:1, v/v). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by preparative TLC (chloroform:methanol=20:1, v/v) and lyophilized from dioxane to obtain the title compound (37.6 mg, 38.5%, for the three steps) as yellow orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 79.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{1-[5-(4-chlorophenyl)-2-methyl-3-furyl]-3-methylbutoxy}benzoic acid (128 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (124 mg, 86%) as an amorphous compound.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cc1
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (146 mg, 0.47 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.47 mmol) and N,N-dimethylaminopyridine (57.4 mg, 0.47 mmol) in DMF (10 ml) was added EDC.HCl (99.0 mg, 0.52 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (288 mg, 91%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.20 (m, 3 H), 2.34–2.43 (m, 1 H), 3.35 (s, 2 H), 3.72 (s, 3 H), 3.89 (s, 3 H), 4.38–4.49 (m, 2 H), 4.62 (br s, 1 H), 4.94 (t, J=7.2 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.67 (s, 1 H), 6.91–7.05 (m, 4 H), 7.28–7.42 (series of m, 7 H), 7.51 (d, J=8.0 Hz, 2 H), 7.87 (d, J=8.4 Hz, 1 H), 7.99 (d, J=8.8 Hz, 2 H), 8.14 (d, J=8.4 Hz, 2H); MS (ESI) m/z, 672 (M++2), 674 (M++2).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][C:10]([CH3:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCC(C)C>[CH3:9][C:10]1([CH3:12])[O:1][C:2]([C:3](=[O:5])[CH3:4])([CH3:8])[CH2:6][O:7]1
Reactant: CC(=O)C(C)(O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)C
Product: CC(=O)C1(C)COC(C)(C)O1
Yield: 92 %

Procedure:
A mixture of 3,4-dihydroxy-3-methylbutan-2-one (4.13 g, 35 mmol), acetone (25 ml) and p-toluenesulfonic acid monohydrate (33 mg, 0.18 mmol) in isohexane (75 ml) was heated in a Dean-Stark apparatus for 10 h. The solvent was removed by distillation at atmospheric pressure and the residue purified by chromatography on silica gel. Elution with 50% ether in isohexane afforded 1-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)ethanone as a pale yellow liquid (5.1 g, 92%): δH (360 MHz, d6-DMSO) 1.29 (3H, s), 1.34 (3H, s), 1.36 (3H, s), 2.20 (3H, s), 3.69 (1H, d, J 9), 4.18 (1H, d, J 9).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].Cl>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[CH:17]=1
Reactant: COC(=O)CCCBr
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCC1(C(=O)OC)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.81 g (0.183 mol) 50% NaH in 300 ml of DMF was added, dropwise, a solution of 27.5 g (0.131 mol) of methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 100 ml of DMF. After stirring at room temperature for 1 hour, a solution of 33 g (0.183 mol) of methyl 4-bromobutyrate in 25 ml of DMF was added. The resultant homogeneous solution was stirred at room temperature for 16 hours and then poured onto ice/H2O and acidified to pH 3.0 with concentrated HCl. The aqueous was extracted twice with CH2Cl2 and the combined extracts were dried (NaSO4) and filtered. The filtrate was evaporated in vacuo to an oil (44 g) which was purified by column chromatography on 2 Kg of silica gel, eluting with CH2Cl2 /Et2O. Yield 12 g (30%), an oil; NMR (CDCl3) (delta) 1.5-2 6(m, 8H, CH2), 3.62 (s, 3H, CH3), 3.66 (s, 3H, CH3), 4.21 (t, 2H, J=6 Hz, CH2), 6.7-7.4 (m, 3H, arom).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:5]1[C:4]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(Cl)cc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 106.2 %

Procedure:
A suspension of 4-chloro-2-iodo-1-methoxybenzene (2.5 g, 9.3 mmol) and 3-chlorophenylboronic acid (2.2 g, 13.9 mmol) in a mixture of toluene (10 mL), dioxane (10 mL), and 2N Na2CO3 (10 mL) was treated with tetrakis(triphenylphosphine)-palladium (0) (0.54 g, 0.47 mmol), heated to reflux for 16 hours, cooled to room temperature, and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20:1 hexanes/ethyl acetate to provide 2.5 g (100%) of the desired product. MS (DCI/NH3) m/z 254 (M+H)+; 1H NMR (CDCl3) δ 7.75-7.23 (m, 6H), 6.91 (d, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH:1]1([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[CH:1]1([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCc3ccccc32)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)C2CCc3ccccc32)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(1-indanoyloxy)-2-methoxy-benzoate (125 mg, 0.43 mmol) in THF:H2O (1 mL: 0.2 mL) was added LiOH.H2O (35.2 mg, 0.84 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 80:20 hexanes:EtOAc and eluted with 50:50 hexanes:EtOAc. The solvent was removed under reduced pressure to afford 4-(1-indanoyloxy)-2-methoxy-benzoic acid as a foam.