Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.B1([O-])OO1.[OH2:26].[OH2:27].O.O.[Na+].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11]([CH3:12])(=[O:27])=[O:26])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: O
Reactant: CCN(C(=O)CCSC)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(C(=O)CCS(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 60 °C
Yield: 47 %

Procedure:
To N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylthio)propanamide (0.08 g, 0.25 mmol) in glacial acetic acid (0.85 mL) was added sodium perborate tetrahydrate (0.11 g, 0.52 mmol), and the mixture was heated at 60° C. for 1 hour. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 10% methanol/dichloromethane) to give the desired product as a clear oil (0.04, 47%): (thin film) 1661 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (t, J=11.5 Hz, 1H), 8.64 (dd, J=4.8, 1.4 Hz, 1H), 8.17-7.96 (m, 2H), 7.59-7.39 (m, 1H), 3.73 (d, J=7.0 Hz, 2H), 3.44 (dd, J=22.5, 15.7 Hz, 2H), 2.96 (s, 3H), 2.71 (t, J=6.9 Hz, 2H), 1.18 (dd, J=8.8, 5.5 Hz, 3H); ESIMS m/z 357 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1)C>>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(CCC(=O)O)cc2F)n1
Yield: 83.8 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.028 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 83%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:35])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:37]([O:35][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([CH3:44])[CH3:43])[CH3:42]
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A mixture of 3-cyclohexylmethyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.8 Hz, 2H), 7.65 (q, J=8.3 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.72-6.64 (m, 3H), 4.25-4.18 (m, 4H), 2.96 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.38 (t, J=7.3 Hz, 2H), 1.59-1.55 (m, 11H), 1.47-1.42 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.13-1.05 (m, 3H), 0.88-0.75 (m, 2H), MS (ES) m/e 582 (M+1).
Reaction SMILES: B.C([C:5]1[CH:20]=[CH:19][C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=1)C=C.[OH-].[Na+].OO.[O:25]1C[CH2:28][CH2:27][CH2:26]1>CCOCC.O>[CH:6]1[C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9](=[O:18])[C:8]=2[CH:19]=[CH:20][C:5]=1[CH:27]([CH3:28])[CH2:26][OH:25]
Reactant: C1CCOC1
Reactant: C=CCc1ccc2c(=O)c3ccccc3ccc2c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1.67 Ml. of 1.0 molar borane in tetrahydrofuran is added to an ice-cooled solution of 1.23 gm. of 2-(2-propenyl) 5H-dibenzo[a,d]cyclohepten-5-one in 10 ml. of tetrahydrofuran. The mixture is stirred for 2 hours and then 5 ml. of 3.0 molar aqueous sodium hydroxide and 1.5 ml. of 30% hydrogen peroxide are added. The reaction is left for one hour and then water and ether are added. The ethereal layer is washed, dried and evaporated. The product is chromatographed on 50 gm. silica gel, eluting with 1:1 ether/hexane, so as to obtain a 50% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propan-1-ol, m.p. (hexane) 63°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:4]=[C:3]([Cl:12])[C:2]([Cl:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[CH:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)O)C1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 50 °C

Procedure:
1,2-Dichloro-4-fluoro-5-nitrobenzene (0.125 mL, 0.952 mmol) and 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (256 mg, 1.048 mmol) were dissolved in N,N-dimethylformamide (2 mL) and water (1 mL). Triethylamine (0.398 mL, 2.86 mmol) was slowly added. The resulting mixture was heated at 50° C. overnight. The mixture was concentrated and ethyl acetate was added. 1N HCl was then added slowly until the pH=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers were then combined and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 10% to 50% of ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.32 (br, 1H), 8.17 (s, 1H), 7.69 (s, 1H), 3.36-3.90 (m, 4H), 2.97-3.29 (m, 2H), 2.88 (dd, J=8.92, 3.37 Hz, 1H), 2.18-2.47 (m, 2H), 1.41 (s, 9H); MS (DCI+) m/z 434.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCc1cccnc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-pyridinepropanol (10 g), 1,6-dibromohexane (40 ml) 50% (w/v) sodium hydroxide (40 ml) and TAB (1.0 g) was stirred at room temperature for 3 h, water (150 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether (1:1), to give the title compound as a yellow oil (11.0 g), t.l.c. (hexane-ether 1:1) Rf 0.16.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.[CH2:8]([N:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1)[CH2:11][CH3:12])[CH3:9].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>CO.O.C(O)C>[Cl:21][C:22]1[C:23](=[O:28])[CH:24]=[CH:25][C:26](=[N:17][C:16]2[CH:18]=[CH:19][C:13]([N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:20])[CH:27]=1
Reactant: CCN(CC)c1ccc(N)c(C)c1
Reactant: Oc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCN(CC)c1ccc(N=C2C=CC(=O)C(Cl)=C2)c(C)c1
Temperature: 55 °C
Yield: 90 %

Procedure:
1450 parts K3Fe(CN)6, 595 parts Na2CO3, and 4150 parts water were added to a 12-liter round bottom flask equipped with a mechanical stirrer, thermometer, and addition funnel. The mixture was heated to 55° C. with stirring. A solution of 227 parts 4-(N,N-diethylamino)-2-methylaniline monohydrochloride, 128 parts o-chlorophenol, 1960 parts ethanol, and 2500 parts water was charged to the addition funnel and added dropwise to the stirred, heated solution. After the addition was complete the reaction mixture was maintained at 55° C. with stirring for 20 minutes. The warm mixture was filtered with vacuum and the resulting filter cake was placed in a solution of 296 parts ethanol and 1125 parts water to form a slurry. The dye was isolated by vacuum filtration. This process was repeated two times, first with 296 parts ethanol and 1125 parts water, then with 608 parts methanol. After the final vacuum filtration the filter cake was dried at 40° C. under vacuum for 48 hours. Yield was ~90%. The final product can be recrystallized from ethyl acetate or ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.O.O.Cl[Sn]Cl>C1COCC1>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2N)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In aflame dried, round bottom flask, 5-bromo-2-nitro-aniline (2) (10.66 g, 49.09 mmol), (scheme 1, Example 1), and 4-methoxybenzoyl chloride (8.37 g, 49.09 mmol) were added. The mixture was heated to 90° C. The melted solids were stirred overnight to give a yellow-brown solid. THF (250 mL) was then added and the solution was treated with SnCl2.2H2O (55.38 g, 245.45 mmol, 5.0 eq) and stirred at room temperature for 2 hrs. Approx. half of the THF was evaporated then 200 mL of EtOAc and 100 mL sat. NaHCO3 were added. The precipitated tin salt was taken out by filtration and a work-up was done on the filtrate with EtOAc. The combined organic layers were washed with water and brine and dried over MgSO4. Most of the EtOAc was evaporated then hexane was added and the precipitate was collected by filtration to give the title compound 114 as a beige powder (13.40 g, 85% yield). 1H NMR (DMSO-d6) δ(ppm): 9.52 (s, 1H), 7.93 (d, J=9.0 Hz, 2H), 7.34 (d, J=2.3 Hz, 1H), 7.08 (dd. J=8.6, 2.3 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H) 5.10 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=O)[CH:12]([CH3:16])[O:11][C:10]=2[CH:17]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][CH2:13][CH:12]([CH3:16])[O:11][C:10]=2[CH:17]=1
Reactant: CC1Oc2cc(Br)ccc2NC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC1CNc2ccc(Br)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Borane dimethyl sulfide complex (2 M solution in THF, 0.414 mL, 0.828 mmol) was added at room temperature to a solution of 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one A-2 (100.0 mg, 0.414 mmol) in anhydrous THF (4.10 mL) under an atmosphere of argon. The reaction mixture was heated to reflux for 2 h, cooled to room temperature, quenched with methanol (1.0 mL), stirred for 30 mins and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine A-3 (92.9 mg, Yield=98%). MS (ESI) [M+1]+ 228, 230.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](OC)=[O:30])[N:24]=1>C1COCC1>[Br:22][C:23]1[N:24]=[C:25]([C:29](=[O:30])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: COC(=O)c1cccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)n1)C(c1cccnc1)c1cccnc1
Temperature: 25 °C

Procedure:
To a solution of di-3-pyridylmethane (250 mg, 1.47 mmol) in dry TIE (5 mL) was added LDA (2.1 mL, 3.16 mmol) slowly at −78° C. After 30 min a solution of methyl 2-bromopyridine-6-carboxylate (349 mg, 1.62 mmol) in dry THF (3 mL) was added slowly. After 30 min the cooling bath was removed and the mixture allowed to warm to RT. After 4 hr the mixture was diluted with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (100% EtOAc) gave 1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethanone as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 8.66 (m, 2 H), 8.53 (m, 2 H), 8.06 (dd, J=0.98 and 6.35 Hz, 1 H), 7.80 (m, 4 H), 7.28 (m, 2 H), 6.79 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[CH3:14][S:13][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 5.0 g (21.49 mmol) of ethyl 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate and 4.9 mL (53.72 mmol) of aniline in 75 mL of THF are added 7.49 mL (53.72 mmol) of triethylamine. The mixture is stirred at room temperature overnight. After evaporating off the THF, aqueous 1N HCl solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution and then with NaCl solution. The organic phase is dried over MgSO4. After filtering, the filtrate is concentrated to give 3.99 g of the expected product in the form of a beige-coloured solid, which is used as obtained in the following step. Yield=64%.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23][S:32]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=3)(=[O:34])=[O:33])=[C:16]([CH:24]([CH3:25])[CH3:26])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 52.8 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (1.30 g, 2.77 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.00 g, 4.22 mmol). Purification on Dynamax C18 (90% CH3CN/H20) gave 0.98 g (53%) of the title compound as an off white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ1.05 (d, 12 H), 1.80 (s, 3 H), 2.19 (s, 3 H), 3.06 (septet, 2 H), 3.81 (s, 2 H), 6.92 (d 2 H), 7.39 (dd, 2 H), 7.44 (s, 1 H), 7.45 (s, 2 H), 7.48 (d, 1 H), 8.05 (d, 1 H). IR (KBr) 3400, 2950, 1680, 1375 and 1190 cm−1. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.20; H, 4.97; N, 0.00. Found: C, 59.18; H, 5.21; N, 0.08.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: Nc1ccc2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-Boc-Dap-2-AQ (11, 68.0 mg, 0.16 mmol) in CH2Cl2 (4 mL) that was stirring at 0° C. under argon was added trifluoroacetic acid (TFA, 2 mL), and stirring was continued for 2 h with warming to rt. The solvent was removed under vacuum, toluene being used to form an azeotrope with the remaining TFA. The residue, a yellow oil, was allowed to stand under diethyl ether for 1 h. Removal of the ether left a yellowish oily solid to which hexane was added and removed under vacuum until a constant weight was reached (99.4 mg; quantitative), and this material was used immediately in the next reaction.
Reaction SMILES: [CH2:1]([N:4]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:24](O)=[O:25])[CH2:13][C@:14]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:37]([O:44][C:45](=[O:57])[NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][CH:50]=1)=[NH:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@@:14]1([CH3:15])[C:8]2=[N:7][CH:6]=[C:5]([N:4]([CH2:1][CH:2]=[CH2:3])[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:10](=[O:11])[N:9]2[C@@H:12]([C:24](=[O:25])[NH:56][CH2:55][C:52]2[CH:51]=[CH:50][C:49]([C:47]([NH:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:57])=[NH:48])=[CH:54][CH:53]=2)[CH2:13]1)([CH3:21])([CH3:23])[CH3:22]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)O)C[C@@]2(C)CC(=O)OC(C)(C)C
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 63.7 %

Procedure:
Following a procedure similar to that for the preparation of 18 g, intermediate 38c (268.9 mg, 0.54 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester (223.9 mg, 0.70 mmol) to provide 262.3 mg (64%) of intermediate 38d. MS (ESI) 763.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])=[CH:6][C:7]2[C:8]([CH3:16])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[C:5](/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])=[CH:6][C:7]2[C:8]([CH3:16])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc2c(cc1/C(=C\C=C\C(C)=C\C(=O)O)CC)C(C)=CCC2(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of ethyl 7-(3-ethoxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-yl)-3-methyl-nona-2E,4E,6Z-trienoate (Compound A-13, 0.82 g, 2.01 mmol) in ethanol (5 mL) and THF (5 mL) was treated with 2M NaOH (5 mL, 10 mmol) and then stirred at 50° C. for 5 h. The mixture was cooled to room temperature, acidified with 10% HCl, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from acetonitrile to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:14])[CH:3]=1.[BH4-].[Na+].Cl.O>O1CCOCC1.CO>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)Oc1cc(C=O)c(F)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Oc1cc(CO)c(F)cc1Cl
Reaction time: 0.67 h
Yield: 88.5 %

Procedure:
Then, 7.5 g of 4-chloro-2-fluoro-5-isopropoxybenzaldehyde was dissolved in 70 ml of 1,4-dioxane and 5 ml of methanol, to which 0.92 g of sodium borohydride was added at 5° C., and the mixture was stirred for 40 minutes. After completion of the reaction, a small amount of diluted hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@H:29]1(O)[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OC2CCC(O)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 67.9 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis/trans-1,4-cyclohexanediol (586 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (338 mg, 68%). 1H NMR (300 MHz, CDCl3): mixture of diastereoisomers: 7.93-7.90 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.56-7.51 (m, 2H, Ar—H), 7.18-7.02 (m, 7H, Ar—H), 4.78 and 4.24 (d: AB, J=15.0 Hz, 2H, N—CH2); 3.70-3.62 (m, 1H, HOCH—), 3.26-3.09 (m, 1H, OCH), 1.86-1.26 (m, 10H, CH2). 13C NMR (75 MHz, CDCl3): mixture of diastereoisomers: 168.33, 147.16, 146.01, 144.80, 137.66, 134.74, 132.72, 131.58, 130.21, 130.16, 129.68, 128.31, 128.28, 128.23, 128.19, 123.81, 123.09, 94.30, 94.28, 71.41, 69.22, 68.61, 67.66, 42.65, 32.51, 32.32, 30.95, 30.65, 30.33, 29.19, 29.03. m/z (ES): 493 [M+H]+. HPLC: Rt=3.43 min. Anal.: calc. for C27H25ClN2O5+0.1 H2O: C, 65.54; H, 5.14; N, 5.66. Found: C, 65.09; H, 5.20; N, 5.24.