Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:15]O>>[OH:1][C:2]1([C:7]([O:9][CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: O=C(O)C1(O)CCCC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(O)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-hydroxycyclopentanecarboxylic acid (2.00 g) in methanol (15 mL) was added conc. sulfuric acid (0.1 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was diluted with diethylether. The mixture was washed successively with an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give methyl 1-hydroxy-cyclopentanecarboxylate (2.06 g) as a pale brown oil.
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:11][S:10][CH2:9][N:8]1[C:12]([CH:14]1[CH2:18][S:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])=[O:6].[F:26][C:27](I)([F:32])[C:28]([F:31])([F:30])[F:29].C[Li].[Br-].[Li+]>C(OCC)C>[F:26][C:27]([F:32])([C:28]([F:31])([F:30])[F:29])[C:5]([CH:7]1[CH2:11][S:10][CH2:9][N:8]1[C:12]([CH:14]1[CH2:18][S:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:13])=[O:6]
Reactant: FC(F)(F)C(F)(F)I
Reactant: COCNC(=O)C1CSCN1C(=O)C1CSCN1C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CSCC1C(=O)N1CSCC1C(=O)C(F)(F)C(F)(F)F
Yield: 89.9 %

Procedure:
To a stirred solution of 4-[[4-[(methoxymethylamino)carbonyl]-3-thiazolidinyl]carbonyl]-3-thiazolidine carboxylic acid, 1,1-dimethylethyl ester (compound from Example IIID; 0.33 g, 0.84 mmol) in ethyl ether (30 ml) under argon at -78° C. was added perfluoroethyl iodide (0.32 ml, 2.70 mmol) followed by methyl lithium.lithium bromide (1.57 ml, 2.36 mmol, 1.5M in ethyl ether). TLC indicated the reaction was complete. The reaction was poured into 100 ml ethyl ether containing 25 g silica gel. Residual amounts of product in the flask were dissolved in ethyl ether and added to the silica/ether solution. Subsequently, the organic phase was removed and the silica gel was washed with ethyl ether (2×100 ml). The combined organics were dried over magnesium and sodium sulfate and then filtered and evaporated to give an oily white foam (0.34 g). The material was then flash chromatographed on a 4×10 cm silica gel column eluting with 0.4 liter of ethyl acetate/hexane (30:70) followed by 0.5 liter of ethyl acetate/hexane (75:25). Product containing fractions were combined and concentrated to an oil (49 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O>[CH3:17][C:18]1[N:22]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: Cc1nc2ccccc2[nH]1
Solvent: O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sccc2n1
Temperature: 135 °C
Yield: 28 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (155 mg) and 2-methylbenzimidazole (161 mg) were heated together at 135° C. overnight. The mixture was then cooled, diluted with water and extracted with ethyl acetate. Combined extracts were dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration gave 174 (28%). NMR: (CDCl3): 2.95 (s, 3H, CH3), 3.89-3.91 (m, 4H, 2×CH2), 4.07-4.09 (m, 4H, 2×CH2), 7.25-7.28 (m, 2H, 2×ArH), 7.50 (d, H, ArH, J=5.47 Hz), 7.71 (m, H, ArH), 7.85 (d, H, ArH, J=5.48 Hz), 8.09 (m, H, ArH). MS: (ESI+): MH+=352.13
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH3:21])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N1CCOCC1)C.[CH2:38]([NH2:41])[CH2:39][CH3:40]>O1CCCC1.C(OCC)(=O)C>[CH2:38]([NH:41][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH3:21])[CH2:39][CH3:40]
Reactant: CCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
2 g of 1-(N-(tert-butoxycarbonyl)-2(S)-amino-butyryl)-L-proline (6.6 mmol) prepared as in Example 2 c) are dissolved in tetrahydrofuran (40 ml). 0.86 ml of isobutyl chloroformate (6.6 mmol) and 0.85 ml of N.-ethylmorpholine (6.6 mmol) are then added to this solution, at −10° C. and under nitrogen. After stirring at −10° C. for 20 minutes, 2.75 ml of n-propylamine (33.0 mmol) are added. The mixture is left stirring at 0° C. for one hour and then at room temperature overnight. The solvent is evaporated off under vacuum and a white semi-solid material is obtained. It is dissolved in ethyl acetate (150 ml) and washed with 5% citric acid (30 ml), saturated sodium bicarbonate solution (30 ml) and brine (20 ml). After drying (Na2SO4) the mixture is filtered and the solvent is evaporated off. An oil is obtained, which is purified by liquid chromatography on a column (eluent: ethyl acetate) and a white solid is obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][OH:16])[O:13][CH:12]=[CH:11][C@H:10]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:16][CH2:15][C@H:14]1[O:13][CH:12]=[CH:11][C@@H:10]([OH:17])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
4-O-benzyl-D-glucal (21.2 mmol) and pyridine (45 mmol), were dissolved in dichloromethane (100 mL). Obtained solution was cooled down to 0° C., and acetyl chloride (25 mmol) was added. The mixture was stirred at 0° C. After reaction was completed, the reaction mixture was washed with water (3×50 mL), dried over anhydrous sodium sulfate. Drying agent and solvent were removed and product was purified by column chromatography (Silicagel 60) using hexanes:ethyl acetate as eluents. Yield 50%.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH:13]=1>C(O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22][S:11][C:6]2[CH:7]=[CH:8][C:9]3[C:4](=[CH:3][CH:2]=[CH:1][CH:10]=3)[CH:5]=2)[CH:13]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: C=CC(=O)CCc1cccnc1
Solvent: CCO
Product: O=C(CCSc1ccc2ccccc2c1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thionaphthol was added to a solution of 1-(3-pyridyl)-4-penten-3-one (0.200 g) in ethanol (30 ml) followed by stirring overnight at room temperature. The ethanol was removed under reduced pressure and the residue purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title compound as a white solid (0.142 g).
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3]>O1CCOCC1.CCOCC>[CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]2)[C:2]#[CH:3]
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCOCC
Solvent: C1COCCO1
Product: C#CC[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]12

Procedure:
A mixture of 150 mg of 10-(2-propynyl)-estr-4-ene-3,17-dione, and 300 mg of dichlorodicyanoquinone in 10 ml of dioxane is refluxed for 20 hours. The mixture is cooled and diluted with ether and then washed with aqueous sodium carbonate and dried. The solvent is evaporated and the residue is chromatographed on silica gel in ethyl acetate/hexane to give 10-(2-propynyl)-estra-1,4-diene-3,17-dione melting at about 200°-201° C. This compound has the following structural formula ##STR11##
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:52]([OH:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CN1CCOCC1.CC#N.Cl>C(Cl)Cl.O1CCOCC1>[CH2:52]([O:59][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol), HOBt (98 mg, 726 μmol), and EDCI (128 μL, 726 μmol) were dissolved in DCM (2 mL). After stirring for 15 minutes, benzyl alcohol (200 μL, 1.9 mmol) and 4-methylmorpholine (106 μL, 967 μmol) were added. The resulting mixture was stirred at room temperature overnight, and then the reaction was quenched with water. The DCM layer was separated, concentrated, purified ((Interchim reverse phase chromatography column), and dried under vacuum. The purified material was combined with MeCN (1 mL, 20 mmol) and 4 M HCl in dioxane (240 μL, 970 μmmol) and stirred at room temperature for 1 hour. The solvent was then removed to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Temperature: 55 °C
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.18 g, 0.61 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (0.56 g, 2.44 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.116 g, 75%). LCMS m/z (%)=267 M+H+, (75Cl, 100), 269 (37Cl, 28.5)), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, 2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 31-1).
Reaction SMILES: CO[C:3](OC)([CH3:5])[CH3:4].[O:8]=[CH:9][C@@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2-]C(C)=O.O=C[C@@H]([C@@H]([C@@H](CO)O)O)O.OS(O)(=O)=O.C(N(CC)CC)C>C(O)C.ClCCl.C(O)C.CC(C)=O>[OH:8][CH2:9][CH:10]1[C@H:12]2[O:13][C:3]([CH3:5])([CH3:4])[O:15][C@H:14]2[CH:16]([OH:17])[O:11]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [CH2-]C(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)O[C@@H]2C(CO)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Into a 2000 L reactor was charged acetone (1200 L) and 2,2-dimethoxypropane (125 kg, 1200 mol, 1.2 eq), followed by D-ribose (150 kg, 999 mol). The mixture was stirred at ambient temperature. p-TSA (p-toluene sulfonic acid) (9.6 kg, 49.5 mol, 0.05 eq) was added in portions over 40 minutes. The reaction mixture was heated at 30° C. and monitored by TLC every hour. After 14 hours, TLC indicated complete conversion. A sample from the reaction mixture and standard samples for ribose and ribose acetonide were applied to a commercial silica gel TLC plate, and the plate was run in the mobile phase dichloromethane/ethanol=8:1. The plate was then sprayed with 10% H2SO4 in ethanol and heated using a heat gun. Ribose-related compounds gave dark spots on the plate. The Rf for Ribose was ˜0.1, while Rf for ribose acetonide (1) was usually 0.3˜0.35. To the reaction mixture was added triethylamine (8.1 kg, 0.08 eq). Acetone was distilled under vacuum (water bath temperature<60° C.) over 12 hours. The residue was diluted with dichloromethane (300 L). The mixture was stirred for 0.5 hour at ambient temperature, and then solvent was removed under vacuum over 4 hours. This operation was repeated once, and the residue was used in next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.31 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.59 (dd, J=5.6, 12.0 Hz, 1H, HOCHH), 3.63 (dd, J=4.8, 12.0 Hz, 1H, HOCHH), 4.19 (irregular t, J=4.4, 5.2 Hz, 1H, 4-H), 4.52 (d, J=6.0 Hz, 1H, 3-H), 4.77 (d, J=6.0 Hz, 1H, 2-H), 5.26 (s, 1H, anomeric H). Anal. calcd for C8H14O5: C, 50.52; H, 7.42. Found: C, 50.48; H, 7.36; [α]25D−36.2 (c 1.45, acetone) [lit., [α]25D−37 (c 0.53, acetone)].
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: O=C1CNc2ncc(-c3cccnc3)cc2N1Cc1ccccc1
Yield: 60 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (100 mg) was reacted with 3-pyridine boronic acid as in General Procedure 4A to give the title compound as a light yellow solid (60% yield). M.p. 58° C., LCMS: m/z=317.16 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 4.42 (s, 2H), 7.22-7.31 (m, 2H), 7.32-7.38 (m, 4H), 7.50 (s, 1H), 7.85-7.92 (m, 1H), 8.02 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.65-8.75 (m, 1H), 8.75-8.90 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:5]=2[C@@H:4]2[CH:24]=[C:25]([CH3:28])[CH2:26][CH2:27][C@@H:3]12.C(Cl)(=O)C(Cl)=O.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.Cl>C1C=CC=CC=1.[OH-].[Na+]>[CH3:29][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)=[O:18])[C:5]=2[C@@H:4]2[CH:24]=[C:25]([CH3:28])[CH2:26][CH2:27][C@@H:3]12
Reactant: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCc1cc(OCCCC(=O)NCCc2ccc(O)cc2)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a solution of 1.00 g (2.49 mmol) of (6aR-trans)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid in 4 ml of benzene was added 1.0 ml (1.46 g, 11.4 mmol) of oxalyl chloride. When the evolution of gas ceased, the mixture was heated with an 80° oil, both for 30 min. The excess oxalyl chloride and the benzene were evaporated under vacuum, 2 ml of benzene was added, and this was also evaporated. The residue was dissolved in 2 ml of ether and add with stirring to an ice cold solution of 443 mg (3.23 mmol) of tyramine in 3.25 nl of 1 N sodium hydroxide, while also adding, at the same rate, 2.5 ml of ice cold 1 N sodium hydroxide. The resulting suspension was stirred at ice temperature for one hour, acidified with hydrochloric acid and extracted with ether. The extracts were dried and concentrated, and the residue was chromatographed on silica gel. Elution with 2% methanol in chloroform and concentration of the fractions containing product gave 330 mg (25%) of (6aR-trans)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]-N-[2-(4-hydroxyphenyl)ethyl]butanamide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:24][C:25]=2[O:27][CH:28]([CH3:30])[CH3:29])[N:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56].[I-].[Na+]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34][N:60]3[CH2:61][CH2:62][N:57]([CH:55]=[O:56])[CH2:58][CH2:59]3)=[CH:24][C:25]=2[O:27][CH:28]([CH3:29])[CH3:30])[N:20]=[CH:19][N:18]=1
Reactant: O=CN1CCNCC1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C=O)CC4)cc(OC(C)C)c23)c2c1OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (0.320 g, as a 1:1.3 wt.:wt. mixture with triphenylphosphine) and N-formyl piperazine (0.69 ml) was dissolved in 2-methoxyethanol (7 ml), then sodium iodide (0.040 g) was added and the reaction mixture was then heated at 110° C. with stirring for 24 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (70 ml) and washed with water:brine (1:1) then water then brine and dried over magnesium sulfate before filtration and evaporation of solvents under reduced pressure. The residues so resulting were then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound (0.086 g) as a white foam; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.03 (quin, 2H), 2.47 (dt, 4H), 2.58 (t, 2H), 3.40 (t, 2H), 3.45 (s, 3H), 3.58 (t, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.82 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.83 (d, 1H), 7.06 (s, 1H), 8.03 (s, 1H), 8.51 (s, 1H), 9.41 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:6]=[CH:7][CH:8]=1.[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]2[CH2:22][O:23]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 90 %

Procedure:
Following a procedure similar to that described in Example 1(a), 3.40 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7), 1.5 g of potassium t-butoxide and 3.63 9 of epibromohydrin were reacted in 70 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 3.73 g (yield 90%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17](C1C=C(C=CC=1)C(O)=O)[C:18]1[CH:23]=C[CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:18]([C:19]1[O:12][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[N:13][C:20]=1[CH3:21])(=[O:17])[CH3:23]
Reactant: NC(=O)c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1oc(-c2cccc(Oc3ccccc3)c2)nc1C
Temperature: 180 °C
Reaction time: 23 h
Yield: 94 %

Procedure:
A mixture of 3-phenoxybenzamide (2.13 g, 10 mmol), 3-phenoxybenzoic acid (4.28 g, 20 mmol), and 3-chloropenta-2,4-dione (0.44 g, 3.3 mmol) was heated to 180° C. under stirring for 23 h. The hot mixture was poured into 1N aqueous sodium hydroxide (100 ml), and extracted with diethyl ether (100+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate, and evaporated to dryness. Purification by silica gel column chromatography (135 g, 16.7% ethyl acetate in n-hexane) afforded the titled compound as solids in 94% yield: 1H NMR (CDCl3) δ7.88-7.83 (1H, m), 7.77-7.53 (1H, m), 7.49-7.34 (3H, m), 7.18-7.12 (2H, m), 7.07-7.00 (2H, m), 2.55 (3H, s), 2.54 (3 H, s).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[N:16][OH:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([O:17][N:16]=[C:12]1[C:13](=[O:15])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)ON=C1C(=O)c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
22.3 g (0.1 mole) of 9,10-phenanthrene-dione-9-oxime are reacted with 12 ml (0.11 mole) of n-butyl isocyanate in 100 ml of chloroform in the presence of 0.2 ml of triethyl amine for an hour. The reaction mixture is heated to boiling for half an hour and evaporated in vacuo. Thus 32 g of 9,10-phenanthrene-dione-9-(n-butyl-aminocarbonyl)-oxime are obtained in the form of a yellowish brown oil, yield 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:22])[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[C:13](=O)[CH2:12][CH2:11]1>C1COCC1.C(OC(=O)C)C>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=3)[C:10]([CH3:22])([CH3:9])[CH2:11][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Mg metal (650 mg, 27 mmol) in THF (20 mL) was added 4-bromotoluene (5.3 g, 31 mmol) in THF (40 mL). The mixture was stirred for 2 hours at ambient temperature and heated to 70° C. for 30 minutes. After cooling to ambient temperature, 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A) (2.1 g, 8 mmol), in THF (5 mL) was added and heated to 70° C. for 24 hours. The mixture was cooled to ambient temperature and the reaction was quenched by addition of H2O. The mixture was diluted with ether:ethylacetate (1:1, 100 mL) and washed with saturated NH4Cl (15 mL), water (10 mL) and brine (10 mL). The organic layer was dried with MgSO4. Solvent was removed under reduced pressure to afford the crude product as an oil. The product was dissolved in THF (20 mL). To this solution p-toleune sulfonic acid (pTSA) (35 mg) was added and the mixture was refluxed for 16 hours. The mixture was cooled to ambient temperature, diluted with ethylacetate (160 mL), washed with 10% NaHCO3 (20 mL), brine (20 mL), dried with MgSO4 and the solvent was removed by evaporation. Purification by chromatography on silica gel gave the title compound as a white solid.