Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(C)cc4)co3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2coc(-c3ccc(-c4ccc(C(=O)O)cc4)cc3)n2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 186C (130 mg, 0.34 mmol) in THF (15.0 mL) and methanol (5.0 mL) at room temperature was treated with 2N sodium hydroxide (3.0 mL), stirred for 18 hours, concentrated, treated with water (2.0 mL), and adjusted to pH<7 with 2N HCl. The precipitate was filtered and dried under vacuum to provide the desired product. MS (DCI) m/e 356 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.72 (s, 1H), 8.18-8.15 (m, 2H), 8.08-8.04 (m, 4H), 7.97-7.86 (m, 4H), 7.31-7.28 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][C:13]([OH:15])=O)=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:27]=1[CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][C:13]([NH:29][CH2:28][C:27]3[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:26]=3[O:25][CH3:24])=[O:15])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:6]=2[CH:23]=1
Reactant: Cc1ccccc1-c1c(CC(=O)O)c(=O)oc2ccc(Cl)cc12
Reactant: COc1cccc(OC)c1CN
Product: COc1cccc(OC)c1CNC(=O)Cc1c(-c2ccccc2C)c2cc(Cl)ccc2oc1=O

Procedure:
6-Chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-acetic acid was reacted with 2,6-dimethoxybenzylamine by a method similar to Example 1(A) to yield the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[C:12]([C:19](=O)[CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[ClH:27].[C:22]([NH:25][N:26]=[C:16]([C:14]1[CH:13]=[C:12]([C:19](=[N:26][NH:25][C:22](=[NH:23])[NH2:24])[CH3:20])[CH:11]=[C:10]([CH:15]=1)[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17])(=[NH:24])[NH2:23]
Reactant: N=C(N)NN
Reactant: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc(NC(=O)c2ccccc2)cc(C(C)=NNC(=N)N)c1
Yield: 97 %

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with 1 mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188°-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetylaniline bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268°-72° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](O)=[C:13]([C:15]2([CH2:32][OH:33])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:33][CH2:32][C:15]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[C:16]3=[O:31])[C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(CO)c1cc(OCc2ccccc2)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
To a stirred solution of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxymethyl-1,3-dihydro-2H-indol-2-one (2.71 g, 5.52 mmol) in anhydrous tetrahydrofuran (60 mL) was added dropwise tributylphosphine (1.39 g, 6.90 mmol). The solution was cooled to 0° C. and di-tert-butyl azodicarboxylate (1.59 g, 6.90 mmol) was added. The solution was stirred at 0° C. for 20 min then quenched with aqueous 10% hydrochloric acid (50 mL). The aqueous solution was extracted with ethyl acetate (3×100 mL), brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography with ethyl acetate in hexanes (20%) to give 5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.36 g, 90%) as a colorless solid: mp 132-135° C.; 1H NMR (300 MHz, DMSO-d6) 7.33-7.21 (m, 7H), 7.16-7.12 (m, 2H), 7.02 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.97 (d, J=3.8 Hz, 1H), 6.90-6.32 (m, 2H), 6.21 (d, J=2.3 Hz, 1H), 5.05 (ABq, 2H), 4.82 (s, 2H), 4.72 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.6, 155.0, 153.6, 141.9, 138.6, 137.4, 132.0 130.3, 129.4, 128.8, 128.2, 128.1, 127.9, 127.1, 124.3, 123.8, 116.6, 110.8, 110.0, 109.9, 79.4, 70.4, 58.1, 38.9; MS (ES+) m/z 476.3 (M+1), 474.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH2:10](Br)[C:11]#[CH:12]>[OH-].[Na+]>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1)[C:11]#[CH:10]
Reactant: OCc1cccc(O)c1
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Product: C#CCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.4 %

Procedure:
To an aqueous solution of 3-hydroxybenzyl alcohol (2.00 g, 16.1 mmol) in sodium hydroxide (35 mL, 1.5 M) was added propargyl bromide (2.11 g, 17.7 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with diethyl ether and washed with a 1.5 M aqueous sodium hydroxide solution and saturated brine, and the organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (0.82 g, yield 31%) as an oily matter.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=O)c(-c3ccnn3C)c2)c1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added acetyl chloride (6.35 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 54.3% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.97 (s, 3H), 3.49-3.56 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.09 (t, J=5.05 Hz, 2 H), 6.36 (t, J=6.32 Hz, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=8.59 Hz, 1 H), 7.09-7.13 (m, 1 H), 7.36-7.45 (m, 2 H), 7.61 (dd, J=9.09, 2.53 Hz, 1H), 7.69 (d, J=1.52 Hz, 1 H), 7.75 (d, J=2.02 Hz, 2 H), 7.85 (s, 1 H).
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:67])[N:62]([CH2:64][C:65]#[N:66])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:68]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:67])[N:62]([CH2:64][C:65]#[N:66])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:68]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC#N)c3=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: N#CCn1nc2n(c1=O)-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Yield: 94.3 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-(cyanomethyl)-1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (45 mg, 0.08 mmol) was reacted to afford the title compound (34 mg, 61%). LCMS (Method D): RT=0.777 min, M-NH2=434. 1H NMR (500 MHz, MeOD): 8.54 (1H, s), 7.45 (2H, d), 7.41 (2H, d), 7.33-7.31 (3H, m), 7.24-7.23 (m, 2H), 5.47 (2H, s), 5.01 (2H, s), 2.78-2.72 (m, 2H), 2.59-2.53 (m, 2H), 2.25-2.18 (m, 1H), 1.99-1.91 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1.[CH3:30][NH2:31].[I-].[Na+]>C(#N)C>[CH3:30][NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CNCCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with methylamine (1M in THF, 1 ml) and sodium iodide (5 mg) and 24 hours. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 401.47 (C24H23N3O3); MS (ESI): 402 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[I-].ClC1C=CC=C[N+]=1C.[OH:27][C:28]1[C:29]([CH3:44])=[C:30]2[C:35](=[C:36]([CH3:39])[C:37]=1[CH3:38])[O:34][C:33]([CH3:43])([C:40](O)=[O:41])[CH2:32][CH2:31]2.CCCCCC>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:17][C:40]([C:33]1([CH3:43])[CH2:32][CH2:31][C:30]2[C:35](=[C:36]([CH3:39])[C:37]([CH3:38])=[C:28]([OH:27])[C:29]=2[CH3:44])[O:34]1)=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CCCCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Under electromagnetic stirring, to a 100 mL reaction flask hexadecanol (970 mg, 4 mmol), 4-dimethylaminopyridine (1466 mg, 12 mmo), 2-chloro-1-methylpyridinium iodide (1533 mg, 6 mmol) and dioxane (20 mL) were added, and then to the reaction solution a solution of (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1001 mg, 4 mmol) in dioxane (20 mL) was slowly dropwise added. The reaction mixture was reacted for 12 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. The solvent (dioxane) was removed by a rotary evaporator, and thereto diethyl ether (50 mL) was added. The resulting mixture was stirred for 2 h, and the precipitate was removed by filtration. The filtrate was concentrated to 10 mL, and isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, the eluent was hexane:ethyl acetate=10:1), to obtain (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester (1242 mg, yield 65.4%).
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[N+:27]([C:30]1[C:31]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:32]([S:39][CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36])([O-])=O>>[NH2:27][C:30]1[C:31]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:32]([S:39][CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: O=C(O)c1cc(SCc2ccsc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(=O)O)cc(SCc2ccsc2)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-(3-thenylthio)benzoic acid, and following the procedure described, 5-amino-4-phenyl-3-(3-thenylthio)benzoic acid is obtained with a melting point of 142°-145° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][C@@H:15]([OH:42])[C@@H:16]([NH:30][C:31](=[O:41])[O:32][C@@H:33]3[C@H:40]4[C@H:36]([O:37][CH2:38][CH2:39]4)[O:35][CH2:34]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:47][N:48]=[C:49]=[O:50].ClCCl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][C@@H:15]([OH:42])[C@@H:16]([NH:30][C:31](=[O:41])[O:32][C@@H:33]3[C@H:40]4[C@H:36]([O:37][CH2:38][CH2:39]4)[O:35][CH2:34]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:49]([NH:48][CH3:47])=[O:50])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN=C=O
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Product: CNC(=O)OCCCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(4-hydroxybutoxy)benzyl]propylcarbamate was treated with methyl isocyanate/dichloromethane as described earlier to afford the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.6-1.8 (4H, m), 1.9-2.0 (1H, m), 2.38 (1H, t), 2.5 (3H, d), 2.7-2.8 (3H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.3-3.4 (1H, m), 34-3.5 (1H, m), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 3.95 (2H, t), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 6.9 (1H, br s), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.25 (1H, s), 7.3 (1H, d); MS: 744 (M+23); C34H47N3O12S.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=O)[CH:8]=2)[CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.O>[OH:1][C:2]1[C:11]([C:12]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][C:21]=2[CH3:26])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][C:21]=3[CH3:26])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: Cc1ccc(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: ClP(Cl)Cl
Product: Cc1ccc(NC(=O)c2ccc3cc(O)c(C(=O)Nc4ccc(C)cc4C)cc3c2)c(C)c1
Temperature: 90 °C
Yield: 58.9 %

Procedure:
2-Hydroxy-3,6-dihydroxycarbonylnaphthalene (11.6 g) and m-xylidine (13.3 g) were dispersed in xylene (232.2 g), followed by heating to 90° C. Phosphorous trichloride (6.0 g) was added dropwise at 90° to 100° C., and then the mixture was reacted at 140° C. for 3 hours. After the completion of the reaction, water (116.1 g) was added and the reaction solution was neutralized with sodium carbonate at 80° to 90° C. The solution was filtered at room temperature and washed in turn with xylene (116.1 g) and water (116.1 g). The resultant crystal was subjected to reflux washing using acetone (80 g) and then filtered. This operation was repeated three times, followed by drying to obtain 12.9 g of 2-hydroxy-3,6-bis(2,4-dimethylphenylaminocarbonyl)naphthalene as a white powdered crystal (melting point: 284.5°-286° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:13]1([O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methoxy-5-nitrophenol (4.86 g), cyclopentyl bromide (3.4 ml) and potassium carbonate (4.8 g) in N,N-dimethylformamide (50 ml) was stirred at 50° C. for 3 hours. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-cyclopentyloxy-4-methoxy-1-nitrobenzene (5.05 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[NH:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: NCC1CCNCC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCC1CCNCC1)c1ccccc1

Procedure:
Benzaldehyde (12.7 g; 0.12 mol) was added dropwise to a solution of 4-aminomethylpiperidine (13.7 g; 0.12 mol) in toluene (50 ml).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:6]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Iodo-1H-pyrazole (2.0 g, 10.3 mmol), 4-methoxy-benzyl bromide (3.0 mL, 20.6 mmol), and cesium carbonate (5.0 g, 15.5 mmol) were combined in DMF (20 mL) and stirred at room temperature for 30 minutes. The mixture was subjected to standard aqueous workup, and the crude residue was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:27])[C@H:15]([CH:24]([CH3:26])[CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[C:17]([NH:16][C@H:15]([C:14]([O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:28])=[O:8])=[O:27])[CH:24]([CH3:26])[CH3:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4-(N-Boc-L-valyloxy)butyric acid benzyl ester (1.2 g, 3 mmole) in ethyl acetate/methanol (5 ml/5 ml) was added palladium black (20 mg). The reaction mixture was kept under hydrogen at atmospheric pressure for 2 hr. The suspension was filtered through Celite and dried, giving the title product, 840 mg.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([F:21])[CH:12]=2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
3-Cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (90 mg, 0.274 mmol) and methyl urea (61 mg, 0.822 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 1.0 mL, 0.685 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 24 h. The resulting cloudy, white reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3-fluoro4-methanesulfonyl-phenyl)-propionyl]-3-methyl-urea (23.3 mg, 23%) as a white solid: mp 199-200° C.; EI-HRMS m/e calcd for C17H23FN2O4S (M+) 370.1362, found 370.1370.
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1(P(=O)(C2C=CC=CC=2)COC)C=CC=CC=1.[CH3:31][C:32]([CH3:38])([CH2:35][CH:36]=[CH2:37])[CH:33]=O>O>[CH3:2][O:1][CH:5]=[CH:33][C:32]([CH3:31])([CH3:38])[CH2:35][CH:36]=[CH2:37]
Reactant: C1CCOC1
Reactant: C=CCC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: COCP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: O
Product: C=CCC(C)(C)C=COC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a freshly prepared tetrahydrofuran (300 mL) solution of lithium diisopropylamide (0.19 mol) under nitrogen at 0° C. was added dropwise in 30 minutes a tetrahydrofuran (200 mL) solution of diphenyl(methoxymethyl)phosphinoxide (49.5 g, 0.2 mol). After stirring for 15 minutes at 0° C., a tetrahydrofuran (100 mL) solution of 2,2-dimethylpent-4-enal (24.5 g, 0.22 mol) was added dropwise in 20 minutes to the cherry-colored mixture. After 15 minutes, the mixture was warmed to room temperature and then refluxed for 5 hours. The mixture was cooled to room temperature, charged with water (20 mL), and cooled at 0° C. under vigorous stirring. The resulting solid was filtered, washed with hexanes, and discarded. The filtrates were collected and distilled at 101-102° C. (155 mmHg) to give the title compound as a colorless oil.