Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C.CCOC(C)=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[CH:22][CH:23]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 30 mL acetonitrile is added 0.22 mL (1.79 mmol) 1-bromomethyl-4-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5.0 mL DMF is added and the reaction mixture is stirred additional 24 h at RT. The reaction mixture is diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: Fc1cc(F)cc(CBr)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Temperature: 100 °C
Yield: 129.8 %

Procedure:
3-Cyano-4-fluorophenylboronic acid (1.649 g, 10 mmol), powdered potassium phosphate (4.254 g, 20 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were charged in an oven-dried flask under argon atmosphere. The flask was evacuated and back-filled with argon thrice and then toluene (30 mL) and 3,5-difluorobenzyl bromide (1.295 mL, 10 mmol) were added by means of a syringe through a lattice stopper, under good stirring. The reaction mixture was heated to 100° C. in half an hour and maintained at that temperature for 1.5 hours. The black mixture was taken up with diethylether (200 mL), washed with saturated aqueous ammonium chloride (2×20 mL), brine (3×30 mL), dried over sodium sulphate and evaporated to dryness to afford 3.21 g of yellow oil. The crude was purified by flash chromatography on silica gel eluting with n-hexane/ethyl acetate 95:5 to yield 1.89 g (yield 76.4%) of whitish solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:14](=O)([O:17]C)[O:15][CH3:16].[H-].[Na+]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH:9]([C:14]([O:15][CH3:16])=[O:17])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCOc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
To a solution of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one from step H2 (5.41 g, 22.4 mmol) in dimethyl carbonate (28.3 ml, 337 mmol) was slowly added a sodium hydride dispersion in mineral oil (2.69 g, 112 mmol). The mixture was stirred at rt for 15 min, then at 80° C. for 2 h. The mixture was then cooled to rt and stirred for 16 h. The mixture was concentrated in vacuo and diethyl ether (150 mL) of was added. The organic layer was washed with of 1 N HCl (100 mL) followed by water, and dried over sodium sulfate. The solvent was removed in vacuo. The crude product was purified by silica-gel column chromatography (10-40% EtOAc/hexanes, linear gradient) to afford methyl 7-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-4-carboxylate (3.32 g, 11.1 mmol, 50% yield) as a white solid. LCMS (M+H)+=300.95. 1H NMR (500 MHz, chloroform-d) δ 7.91 (d, J=2.4 Hz, 1H), 7.61-7.48 (m, 1H), 7.03-6.89 (m, 1H), 4.49 (ddd, J=12.4, 6.7, 3.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.77 (s, 3H), 2.68-2.47 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.C([O:32][CH2:33][C:34](Cl)=[O:35])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:7]3[CH2:6][C:5]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:8]=3[N:9]([C:33](=[O:32])[CH2:34][OH:35])[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)CO)C2
Yield: 90 %

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (3.6 g, 10.0 mmol), Benzyloxy-acetyl chloride (Compound 27a) (2.2 g, 12.0 mmole) and DMF (50 mL) was added Diisopropylethylamine (5.2 mL, 30 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc. Dried over sodium sulfate and removed solvent in vacuo. The crude material was then taken up into ethanol and 0.5 g of Pd/C was added. The reaction was shaken on the hydrogenator over night. The reaction was filtered through Celite and removed solvent in vacuo. Triturated in a small amount of EtOAc. 3.2 g of ˜90% pure material was produced. 300 mg of the crude material was prepped on the Gilson and lyophilization gave Compound 432 as a white powder. MS m/z 384 (M+H)+;
Reaction SMILES: [C:1](=[O:17])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+]([O-])=O)=CC=1)OCCCC.[NH2:18][C:19](=[NH:49])[C:20]1[CH:48]=[CH:47][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]3[CH:46]=[CH:45][C:41]([C:42]([NH2:44])=[NH:43])=[CH:40][CH:39]=3)[CH2:30][CH2:29]2)=[CH:22][CH:21]=1.C(Cl)(Cl)Cl.[OH2:54]>CN(C)C=O>[NH2:49][C:19](=[N:18][C:1]([O:7][CH2:8][CH2:13][CH2:12][CH3:11])=[O:17])[C:20]1[CH:48]=[CH:47][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([NH2:44])=[N:43][C:1]([O:7][CH2:8][CH2:13][CH2:12][CH3:11])=[O:54])=[CH:45][CH:46]=3)[CH2:30][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Reactant: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NC(=O)OCCCC)cc3)CC2)cc1
Reaction time: 2 h

Procedure:
Into a solution of 1.82 g of butyl 4-nitrophenyl carbonate in 15 mL of N,N-dimethylformamide, 1.50 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine was added at room temperature, and the solution was stirred at the same temperature for 2 hours. Chloroform and water were added to the reaction mixture. The organic layer was separated, washed twice with a 5% potassium carbonate aqueous solution and with a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate, followed by solvent removal by evaporation under reduced pressure. The obtained residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=4:1). The obtained solid substance was dissolved in chloroform, washed twice with a 5% potassium carbonate aqueous solution and with a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation under reduced pressure, 1.39 g of 4-{3-[4-(3-{4-[amino(butoxycarbonylimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-(butoxycarbonyl)benzamidine was obtained as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: CC(C)(C)N=C=O
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Yield: 44 %

Procedure:
A solution of 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) (0.29 mmol), tert-butyl isocyanate (0.29 mmol) and triethylamine (0.58 mmol) in dichloromethane (3 mL) was shaken at room temperature overnight, quenched with water, filtered through a PTFE phase separator cartridge and reduced in vacuo to yield a colourless gum (52 mg, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si](C(C)(C)C)(C)C)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To an ice cooled solution of 12.9 g (38.7 mmol) [5-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester in 130 ml of THF was added 12.45 g (38.7 mmol) of tetrabutylammonium fluoride hydrate. The reaction mixture was stirred for 1 h at RT, taken up in ether and washed with 1N HCl and water. Evaporation of the solvent under reduced pressure gave 7.07 g (83%) of pure (5-hydroxy-indol-1-yl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1](N(CC)CC)C.[F:8][C:9]([F:27])([F:26])[C:10]1[S:14][C:13]([NH:15][C:16](=[S:25])[S:17][CH2:18][CH2:19][C:20]([F:24])=[C:21]([F:23])[F:22])=[N:12][N:11]=1.CI>CN(C)C=O.O>[CH3:1][N:15]([C:13]1[S:14][C:10]([C:9]([F:8])([F:26])[F:27])=[N:11][N:12]=1)[C:16](=[S:25])[S:17][CH2:18][CH2:19][C:20]([F:24])=[C:21]([F:23])[F:22]
Reactant: CCN(CC)CC
Reactant: FC(F)=C(F)CCSC(=S)Nc1nnc(C(F)(F)F)s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=S)SCCC(F)=C(F)F)c1nnc(C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Triethylamine (0.69 gram, 0.0068 mole) was added to a stirred solution of (3,4,4-trifluoro-3-butenyl) N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-dithiocarbamate (2.0 grams, 0.0057 mole) in dimethylformamide (5.7 ml) at ambient temperature. After addition was complete, the reaction mixture stirred for one hour and was then cooled to 0° C. Methyl iodide (1.0 gram, 0.0063 mole) was added to the cooled mixture. After warming to ambient temperature, the reaction mixture was stirred overnight. The reaction mixture was diluted with water (200 ml) and extracted three times with diethyl ether. The combined extracts were washed with 10% aqueous hydrochloric acid. The dried (magnesium sulfate) extracts were concentrated under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, eluting with hexane to yield the first product (3,4,4-trifluoro-3-butenyl) N-(methyl)-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)dithiocarbamate (0.45 gram) as a yellow oil. Eluting solvent was then changed to hexane:ethyl acetate (1:1) to yield the second product methyl(3,4,4-trifluoro-3-butenyl) N-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)imidodithiocarbonate (0.96 gram) as an orange oil. The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([OH:15])[CH:14]=1.Br[C:18]1[CH:19]=[C:20]([O:24][CH2:25][CH3:26])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(=O)C.CN(C=O)C.O>[CH3:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][C:13]=1[O:15][CH2:26][CH2:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)cc1O
Reactant: CCOc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C)c(OCCOc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (1.25 mL, 12.2 mmol) was added to a solution of 5-amino-2-methyl phenol (1.0 g, 8.1 mmol) in acetic acid (6 mL), and the reaction was refluxed for 5 mins. Then the reaction mixture was cooled to room temperature and the product was solidified. It was filtered off and washed with water (4 mL) and dried to obtain the product along with the trace amount of O-acylated product. The mixture, to which was added 3-bromophenetole (1.33 g, 6.6 mmol) and Cs2CO3 (2.927 g, 9.0 mmol) in DMF (10 mL), was stirred overnight at 50° C. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and recrystallized from toluene to obtain the pure product 18a in 65% (yield over two steps) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH2:27][NH:28][OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([N:35]=[C:36]=[O:37])(C)C>O1CCOCC1.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH2:27][N:28]([C:36]([NH2:35])=[O:37])[OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4'-fluoro-4-biphenylylmethyl)-6-[2-(N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (~22.5 mmol) in 1,4-dioxane (50 ml) and methylene chloride (30 ml), is added trimethylsilylisocyanate (3.36 ml). The reaction mixture is stirred at room temperature overnight and is subsequently diluted with H2O (500 ml). The resulting solution is extracted with EtOAc (2×400 ml) and the combined EtOAc portions washed with 2N HCl (800 ml), saturated NaCl solution (800 ml), dried over MgSO4, and concentrated in vacuo. The resulting solid is recrystallized from EtOAc/hexanes to give 2-(4'-fluoro-4-biphenylylmethyl)-6-[2-(N-aminocarbonyl-N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 171°-172°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([OH:38])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([O:38][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1.[H-].[Na+].I[CH3:21]>CN(C)C=O.O>[CH3:21][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1
Reactant: CI
Reactant: CCOC(=O)CC1=COc2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1=COc2ccc(OC)cc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.8 g (12.75 mmol) of the ester obtained in Step B are dissolved in 30 ml of anhydrous N,N-dimethylformamide. 0.61 g (16 mmol) of sodium hydride is then added slowly to the reaction mixture previously cooled to 0° C. After 30 minutes of stirring under argon and at 0° C., 2.28 g (16 mmol) of iodomethane are added to the reaction medium. After 4 hours of stirring at ambient temperature, the solvent is evaporated in vacuo; the residue obtained is then taken up in water and then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title ester is obtained pure in the form of a white solid after passage over a silica column (eluant:ethyl acetate/petroleum ether:30/70).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[C:6]([C:14]1[C:15](=[O:25])[CH:16]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CN(C)C=O.O>[C:6]([C:14]12[O:3][CH:19]1[O:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]2=[O:25])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cc(=O)c(C(=O)c2ccccc2)co1
Reactant: CC(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Reaction time: 1 h

Procedure:
Solid sodium acetate (2.0 g) was added to a stirred solution of this ester (5.4 g) in dimethylformamide (80 ml) at 0°-5° C. 30% Hydrogen peroxide solution (10 ml) was added dropwise over 15 minutes and the mixture was stirred for a further 1 hour at 0°-5° C. then slowly diluted with water (240 ml). The solid product was dried and recrystallised from ether-petroleum ether 40°-60° C. to give the epoxide, ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo-[4.1.0]hept-3-ene-3-carboxylate (mp 96°-98° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].CCOCC>CC(O)C.C(Cl)Cl>[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)CCN2c1ncnc2cc(OC)c(OC)cc12
Yield: 95 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 95% yield from 5-methoxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The free-base obtained following column chromatography on silica (45% acetone/hexanes) was dissolved in minimal CH2Cl2 and treated with 1 eq. of methanesulfonic acid in CH2Cl2 followed by dilution with several volumes of ether to precipitate the mesylate salt which was filtered and added in vacuo. (M.P. 285°-292° C. (dec); LC-MS: 338 (MH+); anal. RP18-HPLC RT: 3.82 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>[N+](C)([O-])=O>[C:17]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, 2-methoxynaphthalene (64 g, 0.41 mol) easily available from a reagent manufacturer was dissolved in nitromethane (150 ml) dried with a molecular sieve 3A. Under an ice bath, aluminum chloride (80 g, 0.60 mol) was added. Subsequently, decanoyl chloride (92 ml, 0.45 mol) was dropped into the solution under the ice bath. The solution was stirred under room temperature for 5 hours, and water (100 ml) was dropped into the solution under the ice bath. The reaction solution was extracted with methylene chloride (200 ml×4), and the obtained organic layer was washed with water (100 ml×3). The organic layer was dried with anhydrous magnesium sulfate, and filtered. Then, the solvent was distilled away under reduced pressure. The obtained yellow solid was recrystallized from hexane to obtain 2-decanoyl-6-methoxynaphthalene (102 g, 82%) as a white solid.
Reaction SMILES: C([O:5][C:6]([CH:8]([N:16]1[C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[N:18](C(OC(C)(C)C)=O)[C:17]1=[O:33])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17](=[O:33])[N:16]([CH:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]([OH:7])=[O:5])[C:20]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccccc1)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
950 mg (2.01 mmol) of tert-butyl 3-(1-tert-butoxycarbonyl-2-phenylethyl)-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIh) were dissolved in dichloromethane (10 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 609 mg (96%) of white solid