Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[O:23][C:22](=[O:24])[CH2:21][C:20]1([OH:29])[C:25]([O:27]C)=[O:26]>CO.O>[C:25]([C@:20]1([OH:29])[C@@H:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[O:23][C:22](=[O:24])[CH2:21]1)([OH:27])=[O:26]
Reactant: COC(=O)C1(O)CC(=O)OC1CCCCCCCCc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C[C@](O)(C(=O)O)[C@@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
Aqueous NaOH (1M, 4 ml, 4.0 mmol) was added dropwise to a stirred solution of ±(4R*,5R*,) 5-[8-(2,4-dichlorophenyl)-octyl]-4-hydroxy-4 -methoxycarbonyltetrahydrofuran-2-one (198 mg, 0.474 mmol) in methanol (4 ml) at 0° C. The solution was stirred at room temperature for 24 h, diluted with water, and washed with ether. The aqueous phase was acidified (aqueous HCl), and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum. The crude diacid was stirred with silica gel (3 g), impregnated with 2M aqueous H2SO4 (0.15 ml), in ether for 1 h. The mixture was filtered, and the solvent removed from the filtrate under vacuum to give the title compound (107 mg), (δ 200 MHz, CDCl3) 7.34-7.10 (3H, m), 4.66 (1H, dd), 3.25 (1H, d), 2.77 (1H, d), 2.67 (2H, t), 1.95-1.20 (14H, m), contaminated with a small amount of ±(E) (4R*,5R*) 4-carboxy-5-[8-(2,4-dichlorophenyl)-7-octenyl]-4-hydroxytetrahydrofuran-2-one.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH:8]([CH2:17][OH:18])[O:9][CH2:10]2.I[CH3:20]>O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH:8]([CH2:17][O:18][CH3:20])[O:9][CH2:10]2
Reactant: COc1ccc(OC)c2c1COC(CO)C2
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: C1CCOC1
Product: COCC1Cc2c(OC)ccc(OC)c2CO1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a suspension of sodium hydride (70 mg of 60% in oil; 1.78 mmol) in tetrahydrofuran (3 ml) was added a solution of 5,8-dimethoxy-3-hydroxymethyl-isochroman (330 mg; 1.48 mmol) in 7 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature until H2 evolution ceased (~15 minutes) and iodomethane (500 μl; 5 eq) was added. The mixture was then stirred at room temperature for 30 minutes. Since the reaction was not complete another equivalent of sodium hydride was added along with 20 mg of cesium carbonate. The mixture was stirred for 15 minutes and was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. The crude was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford the title compound (301 mg; 86%):
Reaction SMILES: [CH3:1]/[C:2](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3]\[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([OH:16])[CH:7]=1.[OH-].[K+]>CO>[CH3:1]/[C:2](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3]\[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:16])[CH:7]=1
Reactant: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(O)c1
Yield: 75.6 %

Procedure:
In methanol was dissolved 18.1 g (59.5 mmol) of methyl 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoate, and 30 ml of an aqueous solution of 8.35 g (148 mmol) of potassium hydroxide was added thereto, followed by heating under reflux for 5 hours. Methanol was evaporated, and a 12% hydrochloric acid aqueous solution added to the residue, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate, followed by concentration. The resulting crude product was recrystallized from an ethyl acetate/hexane mixed solvent to obtain 13.06 g (yield: 75%) of 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoic acid represented by the following structural formula (hereinafter referred to as compound 39) as white crystals. The analytical results are shown below. ##STR60##
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19]CC(F)(F)C(F)(F)F)=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=2)[C:3]1=[O:42].CC1(C)N(CCCCCCCCCSCC[C:62]([F:74])([F:73])[C:63]([F:72])([F:71])[C:64]([F:70])([F:69])[C:65]([F:68])([F:67])[F:66])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][C:62]([F:74])([F:73])[C:63]([F:71])([F:72])[C:64]([F:69])([F:70])[C:65]([F:68])([F:67])[F:66])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:39])([F:41])[F:40])[CH:30]=2)[C:3]1=[O:42]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 85 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 14 replacing the compound of Example 1. A pale yellow oil is obtained with a yield of 85% (145 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.Br.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:15])[N:32]3[CH2:31][C:30]4[C:34](=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:38])[F:37])[CH:29]=4)[CH2:33]3)[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 72 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.200 g, 0.604 mmol; Example 58D) and 5-(trifluoromethyl)isoindoline hydrobromide (0.178 g, 0.664 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.160 mL, 0.905 mmol) and the reaction stirred for 3 days. The reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. MS (ESI+) m/z 501.1 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20](F)=[C:19]([F:26])[C:18]=2[F:27])=[CH:13][CH:12]=1.Cl>CCOCC>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]([F:27])=[C:19]([F:26])[C:20]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:21]([F:24])[C:22]=2[F:23])=[CH:15][CH:16]=1
Reactant: Nc1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: [Li]CCCCCCCC
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCc1c(F)c(F)c(-c2ccc(N)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Octyllithium in dry ether (9.5 mL) was added slowly to a solution of 4-amino-2′,3′,4′,5′,6′-pentafluorobiphenyl (1.5 g, 5.79 mmol, Example 9) in dry ether (100 mL) at −78° C. The solution was stirred at this temperature for 2 hours and then allowed to warm to room temperature over a period of 5 hours. Hydrochloric acid (3M, 100 mL) was added and a white solid was precipitated from the solution. The solid was filtered and dried. After sublimation, 4-amino-4′-n-octyl-2′,3′,5′,6′-tetrafluorobiphenyl was obtained as a white solid (1.2 g, 63% yield).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]=O>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=3)[CH3:42])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate and 37% aqueous formaldehyde followed the procedures of Example 66 as an orange solid MS (EI) m/z 555.3 (M+H)+; 1H NMR (DMSO-d6): δ 2.86 (s, 3H), 3.55 (s, 2H), 4.44 (s, 2H), 6.50 (d, J=7.5 Hz, 1H), 6.60-6.65 (m, 2H), 6.98 (d, J=8.1 Hz, 2H), 7.09 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.55 (t, J=6.2 Hz, 1H), 7.64 (d, J=7.0 Hz, 2H), 7.73 (t, J=7.8 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 9.10 (s, 1H), 12.31 (br s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH3:15])C.[O-]CC.[Na+].CO.ClCCl>C(O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]([C:4]([OH:3])=[O:17])=[C:14]([CH3:15])[C:8]=2[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C(=O)O)oc2ccc(Br)cc12
Temperature: 75 °C
Yield: 72 %

Procedure:
A mixture of (2-acetyl-4-bromo-phenoxy)-acetic acid ethyl ester (2.87 g, 9.5 mmol, 1 eq) and sodium ethoxide (0.65 g, 9.5 mmol, 1 eq) in 100 mL of ethanol under nitrogen was heated to 75° C. for 3 h. After work up followed by column chromatography (20% MeOH/dichloromethane), 5-bromo-3-methyl-benzofuran-2-carboxylic acid was obtained in 72% yield (1.74 g). 1H NMR (400 MHz, CD3OD) δ ppm 2.5 (s, 3 H) 7.5 (d, J=8.8 Hz, 1 H) 7.6 (m, 1 H) 7.9 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][C:27]=3[O:29][CH3:30])[C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16]
Reactant: CCCNC(=O)c1nnc2c(Br)c(C#N)ccc2c1N
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)c(C#N)ccc2c1N

Procedure:
Using Method G, 4-amino-8-bromo-7-cyano-N-propyl-cinnoline-3-carboxamide and 2,4-dimethoxyphenyl boronic acid were reacted to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.51 (br, 1H), 7.87 (m, 2H), 7.27 (m, 1H), 6.66 (m, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.45 (m, 2H), 1.64 (apparent sextet, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=392 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:33])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:39]1[N:43]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[N:42]=[CH:41][CH:40]=1)CCC>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:8](=[O:22])[N:6]3[CH:7]=[C:2]([C:39]4[N:43]([C:44]5[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=5)[N:42]=[CH:41][CH:40]=4)[C:3]([CH3:33])=[C:4]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[C:5]3=[N:10]2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-2-(4-methanesulfonyl-benzyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Int. 16, 45 mg, 0.083 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 69 mg, 0.15 mmol) by a similar method to that used in Example 1 (Step 4) (24 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)CC[CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:36]1([NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]3)[CH:29]=[N:30]2)[CH2:37][CH2:43][CH2:42]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: NC1CCC1
Solvent: NCCO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNC5CCC5)c4)cc23)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 10 mg of the title compound (38%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[O:32])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:18][CH:17]=1.C(O)C.[BH4-].[Na+].Cl>O1CCCC1.O>[OH:32][CH:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:6][C:2]=1[CH3:1])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(O)COc1ccc(CCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of 5-[3-(4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxyjphenyl]propyl]-2,4-oxazolidinedione (0.2 g) in tetrahydrofuran (THF) (5 ml)-ethanol (5 ml) was added sodium borohydride (0.03 g). The mixture was stirred for one hour at room temperature. To the reaction mixture were added 2N HCl and water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography. From the reactions eluted with chloroform-methanol (50:1, v/v) was obtained 5-[3-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-phenyl]propyl]-2,4-oxazolidinedione (0.16 g, 80%). Recrystallization from dichloromethane-isopropyl ether gave colorless needles, m.p.146-147° C.
Reaction SMILES: C(C1C=CC(C(OC(C)(C)C)=O)=CC=1)(=O)C.[C:17]([C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH2:18][CH3:19]>>[OH:20][C@H:17]([C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[CH:23][CH:22]=1)[CH2:18][CH3:19]
Reactant: CCC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Product: CC[C@H](O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Instead of the starting material of Reference Example 1, that is, tert-butyl 4-acetylbenzoate, tert-butyl 4-propionylbenzoate was used for a similar procedure as in Reference Example 1 to obtain tert-butyl 4-[(1S)-1-hydroxypropyl]benzoate (compound S3a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([I:17])[N:14](S(C4C=CC=CC=4)(=O)=O)[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([I:17])[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(I)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of Example 3C (3.5 g, 6.78 mmol) in 70 mL dioxane was treated with aqueous sodium hydroxide (11.30 mL, 67.8 mmol, 6 M) and stirred at 100° C. for 1 hour. The reaction mixture was cooled and diluted with 300 mL of water. The aqueous mixture was extracted with ethyl acetate (3×), and the combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated to give the title compound. MS (ESI+) m/z 370.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: ClCCCCBr
Product: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety -E-G-C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][OH:22])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(Cl)(Cl)Cl>Cl>[CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [K]
Solvent: ClC(Cl)Cl
Product: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
To 21.4 gm. of 1-benzyl-4-hydroxymethyl-5-(3methoxyphenyl)pyrrolidin-2-one in 40 ml. of potassium dried pyridine was slowly added at -4° to -7°, 14.4 gm of p-toluenesulfonyl chloride. The reaction mixture was stirred for 3 hours at 15° and then diluted with 180 ml of 10% hydrochloric acid. The gum was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to provide 24.6 gm. of the desired products as an oil. ir (CHCl3): 1165-1195 cm-1 ; 1335-1375 cm-1
Reaction SMILES: [CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>O.CO>[CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCSC(c1ccccc1)C1(OC)CCOCC1
Solvent: CO
Solvent: O
Product: COC1(C(SCCC(=O)O)c2ccccc2)CCOCC1
Yield: 103.6 %

Procedure:
A solution of methyl 3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl-thio]propionate (Step 1) (0.91 g, 2.8 mmol) and LiCH (0.29 g, 7.01 mmol) in 10% water and methanol (10 mL) was stirred for 18 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). The organic layer was separated and washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 0.9 g of 3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid as a clear, colorless oil: HRMS calcd for C16H22O4S 310.1239, found 310.1241.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>C1COCC1.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Yield: 70.9 %

Procedure:
3-(3-Nitrophenyl)methyl-indole-N-acetic Acid, ethyl ester (0.175 g, 0.5 mmol) was dissolved in THF:EtOH (1:4, 5 mL) at room temperature with stirring. The mixture was cooled to 0° C. and treated with 1N NaOH (1.55 mL, 1.6 mmol). The mixture was allowed to stir at this temperature for 2 h. 1 N HCl was added and the mixture extracted with EtOAc (2×). The organics were combined and washed with a sat'd brine solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with heptane and vacuum-filtered with several heptane washings to give 110 mg (69%) the desired compound as an off-white powder. mp 163-165° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (s, 1 H), 8.03 (d, J=8.1 Hz, 1 H), 7.75 (d, J=8.1 Hz, 1 H), 7.53 (t, J=8.1 Hz, 1 H), 7.45 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 7.20 (s, 1 H), 7.11 (t, J=7.2 Hz, 1 H), 6.97 (t, J=7.2 Hz, 1 H), 4.96 (s, 2 H), 4.18 (s, 2 H); LRMS calcd for C17H14N2O4S: 310.0; found 311 (M+1)+.