Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:52]1([C:58]2([CH2:61][NH2:62])[CH2:60][CH2:59]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.CN(C)C=O>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:62][CH2:61][C:58]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:60][CH2:59]1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: NCC1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)NCC1(c2ccccc2)CC1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 68 %

Procedure:
According to general procedure D, from #11 (2.15 g, 7.48 mmol, 1.1 eq.) in dichloromethane (20 mL, 0.3 M) and N,N-dimethylformamide (4 mL), 1-(1-phenylcyclopropyl)methanamine #@1 (1.001 g, 6.799 mmol, 1 eq.), HATU (3.10 g, 8.16 mmol, 1.2 eq.) and triethylamine (2.84 mL, 20.4 mmol, 3 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), producing #57 (1.93 g, 68%) as a solid. HPLC (Protocol A at 45° C.): m/z 417.3 [M+H+], retention time=10.575 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.75-7.81 (m, 1H), 7.20-7.27 (m, 4H), 7.12-7.19 (m, 1H), 3.33-3.62 and 3.71-3.80 (br multiplets, total 4H), 3.28 (s, 3H), 2.97-3.17 (br m, 2H), 2.14-2.24 (m, 1H), 1.67-1.80 (br m, 2H), 1.45-1.65 (m, 2H), 1.41 (s, 9H), 1.00 (d, J=6.6 Hz, 3H), 0.67-0.93 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:28]([N:12]1[C:13]2[C:9](=[C:8]([CH3:24])[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]([CH3:16])[C:14]=2[NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=[CH:11]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCOC(=O)Cc1c(C)c(NC(=O)C(C)(C)C)c2[nH]ccc2c1C
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
N-(5-Ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (1.45 g) was dissolved in DMF (10 ml) and NaH (P=60%, 132 mg) was added under a nitrogen atmosphere, which was followed by stirring at room temperature for 1 hr. Then, 1-iodooctane (1.06 g) was added and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water. The mixture was extracted with AcOEt (100 ml), washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=1/0−1/1) to give 1.02 g of N-(1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Br[CH2:11][C:12]1[CH:24]=[CH:23][C:15]2[S:16][C:17]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:18][C:14]=2[CH:13]=1>CN(C=O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][C:12]1[CH:24]=[CH:23][C:15]2[S:16][C:17]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:18][C:14]=2[CH:13]=1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Reactant: CN(C)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCSCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a stirred solution of 2-dimethylaminoethanethiol hydrochloride (14.17 g, 0.10 mol) in 125 ml of dry DMF was added portionwise 60% sodium hydride in mineral oil (8.0 g, 0.2 mol) under a nitrogen atmosphere over 1/2 hour with warming on the steam bath. The mixture was stirred an additional 1/2 hour and then cooled in ice. To the cold suspension was added dropwise a solution of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (7.66 g, 0.025 mol) in 25 ml of DMF. The mixture was stirred for an additional 1 hour at ice bath temperature. The mixture was filtered and the filtrate was concentrated in vacuo at 0.5 mm at room temperature. The solid residue was combined with the filtered solid and was dissolved in 3N HCl (100 ml). The acid solution was extracted with CHCl3 (3×50 ml), neutralized with NaHCO3 and concentrated to dryness in vacuo. The residual solid was extracted with CHCl3 (3×100 ml). The CHCl3 extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. The solid obtained contained some polar inpurity which was removed by trituration with hot water. There was recovered 2.8 g of product (Yield 34%); m.p. 132-133%.
Reaction SMILES: [CH:1]1([N:6]2[C:14](=[O:15])[NH:13][C:12]3[C:7]2=[N:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:10][C:11]=3[C:16]([O:18]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28]C1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[CH:1]1([N:6]2[C:14](=[O:15])[NH:13][C:12]3[C:7]2=[N:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:10][C:11]=3[C:16]([NH2:28])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCCC1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(NC2CCCC2)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60 %

Procedure:
Ethyl 9-cyclopentyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-6-(cyclopentylamino)-2-(3-hydroxyphenyl)pyrimidine-4-carboxylate (76.3 mg, 0.223 mmol) was dissolved in methylene chloride (5 ml) and 1,1′-carbonyldiimidazole (361.6 mg, 2.23 mmol) was added. The reaction was refluxed for 1H and then stirred at room temperature for 5 days. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (50% ethyl acetate in hexanes) to provide the title compound (49.7 mg, 0.135 mmol, 60% yield). MS (ESI) m/z 369.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH:5]([O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1>O1CCCC1>[CH3:1][C:2]1[C:3]([C:4]#[C:3][C:2]([CH3:1])=[CH:6][CH2:5][O:7][Si:8]([CH3:11])([CH3:9])[CH3:10])([OH:14])[C:4]([CH3:13])([CH3:12])[CH:5]([O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1
Reactant: CC1=CC(O[Si](C)(C)C)C(C)(C)C1=O
Solvent: C1CCOC1
Product: CC(C#CC1(O)C(C)=CC(O[Si](C)(C)C)C1(C)C)=CCO[Si](C)(C)C

Procedure:
The resulting 2,5,5-trimethyl-4-[(trimethylsilyl)oxyl]-cyclopent-2-en-1-one of formula VI is then condensed in a solvent (e.g. tetrahydrofuran) by means of a Grignard reaction with trimethyl-[(trans-3-methyl-pent-2-en-4-yn-1-yl)oxy]-silane of formula VII to give 5-[2,5,5-trimethyl-1-hydroxy-4-[(trimethylsilyl)oxy]-cyclopent-2-en-1-yl]-3-methyl-1-[(trimethylsilyl)oxy]-pent-2-en-4-yne of formula VIII which, without isolation, is saponified by shaking with a dilute aqueous alkali hydroxide solution to give 5-[1,4-dihydroxy-2,5,5-trimethyl-cyclopent-2-en-1-yl]-trans-3-methyl-pent-2-en-4-yn-1-ol of formula IX.
Reaction SMILES: Br[CH2:2][CH:3]=O.C(OC(OCC)CBr)C.O.O.C(O)(=O)C(O)=O.[Na].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24][C:25]([CH3:27])=O.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>C(O)C>[CH2:30]([O:29][C:23]([C:24]1[CH:3]=[CH:2][N:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:25]=1[CH3:27])=[O:28])[CH3:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=CCBr
Reactant: COc1ccc(N)cc1
Agent: CCOC(CBr)OCC
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccn(-c2ccc(OC)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Bromoacetaldehyde (prepared from the distillates from heating 18.212 g of 2-bromoacetaldehyde diethyl acetal and 25.63 g of oxalic acid dihydrate, see U.S. Pat. No. 4,087,539 for detail) was added to an ice/water bath cooled mixture of ethyl acetoacetate sodium salt (9.84 g) in ethanol (100 mL) carefully; after addition, the mixture was stirred at rt for 1 h and para-anisidine (9.56 g) was added, the resulting mixture was subsequently refluxed in an oil bath for 1 h. Then, reaction was cooled, solvents were removed, the residue was partitioned between EtOAc and 1 M HCl aqueous solution; the organic phase was sequentially washed with water, sat. NaCl solution and dried over anhydrous sodium sulfate, filtered, concentrated; the resulting residue was column-purified to give the desired product (8.08 g). The title compound, ESI MS (m/z): 260 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[O:1]=[C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(Cc2cnccn2)c2ccccc2N1c1ccccc1
Reactant: N#CCCCCBr
Product: N#CCCCCC1(Cc2cnccn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 76 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(2-pyrazinylmethyl)1H-indole and 5-bromovaleronitrile in Example 1, the desired product was obtained in 76% yield as an oil.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][CH2:26][CH2:27][C@H:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][OH:30])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>[Pd].C(O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:23]([NH:25][CH2:26][CH2:27][C@H:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][OH:30])=[O:24])[NH2:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
17 mg of palladium on activated carbon (10%) are added to a mixture of 0.088 g (0.16 mmol) of the compound from Example 238A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22]O)[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][C@@H:19]2[CH2:18][CH2:17][C@H:16]([O:15][CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC[C@@H](OC2CCCCO2)CC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(OC[C@H]2CC[C@@H](OC3CCCCO3)CC2)cc1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
4-Bromophenol (0.344 g, 2.0 mmol) was added to a solution of (+/−)-[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (0.387 g, 1.81 mmol) in THF (10 mL). Triphenylphosphine (0.474 g, 1.81 mmol) and triethylamine (0.183 g, 1.81 mmol) were added. The resulting solution was cooled to 0° C. and DIAD (0.365 g, 1.81 mmol) was added by dropwise addition. After 18 hours the reaction was quenched by addition of water and extracted with ether (2×100 mL). The organic layers were combined and washed with 1N NaOH (2×100 mL) then water (2×100 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a clear oil. Purification by flash column chromatography on a Biotage SNAP cartridge Kp-sil 100 g column (hexanes/ethyl acetate 9:1) afforded the title compound as a white solid (324 mg, 48%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.75 (m, 11H) 1.75-1.98 (m, 4H) 3.39-3.54 (m, 1H) 3.70-3.80 (m, 2H) 3.83-3.97 (m, 2H) 4.55-4.69 (m, 1H) 6.66-6.82 (m, 2H) 7.29-7.42 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NC.[OH:33]N1C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[CH3:50][N:51]1C[CH2:55][O:54][CH2:53][CH2:52]1>CN(C)C=O.ClCCl>[CH3:55][O:54][C:53](=[O:33])[CH2:52][N:51]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[CH3:50]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
(S)-2-(t-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid(0.5 g, 1.72 mmole) was dissolved in dimethylformamide (DMF). The resulting solution was cooled down to 0° C., and then 1-(3-dimethylaminopropyl)-3-methylcarbodiimide hydrochloride(EDC, 0.39 g) and 1-hydroxybenzotriazole(HOBT, 0.28 g) were added thereto and stirred until they are completely dissolved. Separately, the compound(0.35 g, 1.72 mmole) prepared in Preparation 7 was dissolved in dichloromethane(2 ml) and cooled down to -10° C. Trifluoroacetic acid(2 ml) was added thereto and the mixture was stirred for 5 minutes, slowly warmed to room temperature, stirred again for 30 minutes and then distilled under reduced pressure to remove the volatile substance. The resulting compound thus prepared and N-methylmorpholine(1 ml) were added to the solution as obtained above, and then the reaction solution was slowly warmed to room temperature and stirred for 3.5 hours. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile substance. The residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by column chromatography using ethyl acetate/hexane(3/7,by volume) as an eluent to obtain the purified title compound(0.58 g, Yield: 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N+:3]=1[O-].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][O:19][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Product: CC(=O)OCc1ccc(Oc2ccccc2)cn1

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.CN([CH:18]=[O:19])C1C=CC=CC=1.C(Cl)(Cl)=O>>[CH:6]1[C:7]([CH:18]=[O:19])=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc2c(c1)OCO2
Agent: O=C(Cl)Cl
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Into a mixture of 97.6 g (0.80 mole) of 1,2-methylenedioxybenzene and 108 g (0.80 mole) of N-methylformanilide was introduced 87.1 g (0.88 mole) of phosgene at 50° C. over a 1-hour period. Then, the mixture was cooled to 15° C. On the other hand, 29.3 g (0.24 mole) of 1,2-methylenedioxybenzene was charged into another reactor and kept at 90° C. The above mixture was added to this reactor over a 5-hour period. After completion of the addition, the reaction mixture was kept at 90° C. for 30 minutes, poured into ice water, and allowed to stand for 1 hour. Then, the resulting mixture was extracted with toluene. By vacuum distillation, the toluene was removed and the distillate at 84°-85° C./30 mmHg was then collected to recover 63.4 g (0.52 mole) of unreacted 1,2-methylenedioxybenzene. Subsequently, the distillate at 131°-134° C./10 mmHg was collected to obtain 76.8 g (0.512 mole) of piperonal having a purity of 99.5%. The yield (expressed in terms of mole percentage based on the amount of N-methylformanilide used) and selectivity (expressed in terms of mole percentage based on the amount of 1,2-methylenedioxybenzene having reacted) of piperonal were 64.0% and 98.5%, respectively. This product had a melting point of 37° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:69]([C:71]1[CH:78]=[CH:77][C:74]([CH2:75]O)=[CH:73][C:72]=1[F:79])#[N:70].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:68])[N:7]([C@H:34]1[CH2:38][CH2:37][N:36]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:35]1=[O:67])[CH2:8][CH2:9][C:10]1[N:11]([CH2:75][C:74]2[CH:77]=[CH:78][C:71]([C:69]#[N:70])=[C:72]([F:79])[CH:73]=2)[CH:12]=[N:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: CC(C)(C)OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxo-pyrrolidin-3-yl}-{2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}carbamic acid tert-butyl ester, as described above in Step G, (720 mg, 0.785 mmol) and 4-cyano-3-fluorobenzyl alcohol, as described above in Step H, (142 mg, 0.940 mmol) in dry CH2Cl2 (7 mL) were added N,N-diisopropylethylamine (0.342 mL, 1.96 mmol), followed by trifluoromethanesulfonic anhydride (0.158 mL, 0.940 mmol), dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and was stirred for 18 hours, then concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and the resulting solution was stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned between saturated aqueous NaHCO3 (5 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with EtOAc—1% MeOH—0.1% NH4OH to yield the desired product as a pale foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]3OCC[O:20]3)[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)cc1OC
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of compound 6 (5.6 g, 13.23 mmol) in THF (50 mL) at 0° C. was added 2N HCl (50 mL). The resulting mixture was stirred at rt O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 7 (3.0 g, 60%) as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ: 10.35 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.6, 3.1 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.51 (dd, J=8.6, 2.3 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); MS (ES) m/z: 379 (M+1)+, 381 (M+3)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[O:14][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9](=[O:14])[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22]1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNc1nc2ccccc2c(=O)o1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 43.7 %

Procedure:
A mixture of 2-n-heptylamino-4H-3,1-benzoxazin-4-one (3.0 g, 10 mmol) and 4-amino-1-diphenylmethylpiperidine (3.0 g, 10 mmol) in toluene (20 ml) was refluxed for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexane) to give 2-(N'-n-heptylureido)-N-(1-diphenylmethylpiperidin-4-yl)benzamide (2.3 g, 40%): mp 182° C.; 1H NMR (CDCl3)ppm: 0.87 (3H, t), 1.27-1.30 (8H, m), 1.47-1.67 (4H, m), 1.95-2.12 (4H, m), 2.84 (2H, d), 3.24 (2H, q), 3.90-3.94 (1H, m), 4.26 (1H, s), 4.56 (1H, t), 6.09 (1H, d), 6.92-6.98 (1H, m), 7.16-7.44 (12H, m), 8.41 (1H, d), 10.26 (1H, s).