Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH:13]([CH2:23][CH3:24])[CH2:14][S:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][C:21]=2[CH3:22])=[NH:11])[N:3]=[CH:2]1.[C:25](NC(N)=N)#[N:26].[Cl-:31].[NH4+]>>[ClH:31].[ClH:31].[ClH:31].[NH:3]1[CH:2]=[CH:25][N:26]=[C:4]1[CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH:13]([CH2:23][CH3:24])[CH2:14][S:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[CH3:22])=[NH:11]
Reactant: N#CNC(=N)N
Reactant: CCC(CSCc1nc[nH]c1C)NC(=N)NCCCc1c[nH]cn1
Reactant: [Cl-]
Agent: [NH4+]
Product: CCC(CSCc1nc[nH]c1C)NC(=N)NCCCc1ncc[nH]1
Product: Cl

Procedure:
N-[3-(Imidazol-4-yl)propyl]-N'-[1-[(5-methylimidazol-4-yl) methylthio]2-butyl]-guanidine ##STR103## prepared by a method analogous to that of Example 39 from 0.71 g (1.9 mmol) of the previously prepared cyanoguanidine. 0.97 g of a hygroscopic foam composed of equimolar quantities of ammonium chloride and N-[3-(imidazol--yl)propyl]-N'-[1-[(5-methylimidazol-4-yl)methylthio]-2-butyl]-guanidine trihydrochloride is obtained as residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.[CH2:23]([O:25][C:26]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([CH2:28][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Solvent: C1CCOC1
Product: CCOC(=O)CC1OC(=O)c2c(Oc3nc(OC)cc(OC)n3)cccc21

Procedure:
A mixture of 1.5 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy] -3-hydroxy-phthalide (see Example 84) and 2.5 g of (ethoxycarbonylmethylene)-triphenyl-phosphorane is maintained at reflux temperature for 10 hours in approximately 40 ml of tetrahydrofuran. The solvent is then evaporated off and the reaction material which remains is purified on a column of silica gel (eluant: ethyl acetate/n-hexane 1:1) to yield 3-(ethoxycarbonylmethyl)-7[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide, m.p. 150°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:41])[N:24]([CH2:31][C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:18]([O:22][C:23](=[O:41])[N:24]([CH:25]1[CH2:26][CH2:27][N:28]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([CH3:17])=[CH:8][C:9]2=[O:16])[CH2:29][CH2:30]1)[CH2:31][C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CC(=O)Nc4ccccn4)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To 3 mL of dichloromethane solution containing 85 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.12 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(piperidin-4-yl)carbamate and 21 μl of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 0.12 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform : methanol=9:1] to give 0.12 g of tert-butyl(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2-oxo-2-(pyridin-2-ylamino)ethyl)carbamate as a white foam.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1.Cl.C[N:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@H:40]2[CH2:45][CH2:44][C@H:43]([NH2:46])[CH2:42][CH2:41]2)[C:36]1=[O:47])[C:32](=[O:34])[OH:33].[C:48](=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH3:48][O:33][C:32](=[O:34])[NH:31][C@H:35]1[CH2:39][CH2:38][N:37]([C@H:40]2[CH2:45][CH2:44][C@H:43]([NH:46][C:10]3[N:9]=[C:8]([N:7]4[C:6]5[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=5[N:4]=[C:3]4[CH:2]([F:28])[F:1])[CH:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]=3)[CH2:42][CH2:41]2)[C:36]1=[O:47]
Reactant: CS(=O)(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)O)[C@H]1CCN([C@H]2CC[C@H](N)CC2)C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H]1CCN([C@H]2CC[C@H](Nc3nc(N4CCOCC4)cc(-n4c(C(F)F)nc5ccccc54)n3)CC2)C1=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(difluoromethyl)-1-[2-(methylsulfonyl)-6-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazole (200 mg) and methyl[(3S)-1-(trans-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl]carbamate hydrochloride (214 mg), potassium carbonate (135 mg), N-ethyl-N-diisopropylpropan-2-amine (0.38 mL) and N,N-dimethylacetamide (3 mL) was stirred at 100° C. for 6 hours. After leaving to be cooled, to the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol-100:0-80:20) to obtain methyl{(3S)-1-[trans-4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (102 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.S(=O)(=O)(O)O.[N+:18]([O-:21])([OH:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:18]([O-:20])=[O:19])=[C:7]([Cl:11])[CH:6]=1.[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([Cl:11])[CH:8]=[CH:9][C:10]=1[N+:18]([O-:21])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(Cl)ccc1[N+](=O)[O-]
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %
Yield: 33 %

Procedure:
To a solution of (3-chloro-phenyl)acetic acid methyl ester (5.0 g, 27.1 mmol, commercially available) in concentrated sulfuric acid (7.5 mL, 140.7 mmol) at 0° C. was added drop-wise nitric acid (2.52 g, 70%, 28.0 mmol). After stirring at 0° C. for two hrs, the reaction mixture was poured into ice water and was extracted into dichioromethane. The organic extract was washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 6% ethyl acetate in hexane to give the desired (3-chloro-4-nitro-phenyl)acetic acid methyl ester as an oil (2.1 g,33%), and (5chloro-2-nitro-phenyl)acetic acid methyl ester as an oil (3.2 g, 51%). 1H NMR (CDCl3) δ: 3.69 (s, 2H), 3.74 (s, 3H), 7.33 (dd, 1H, J=8.4 Hz, 1.9 Hz), 7.50 (d, 1H, J=1.8 Hz), 7.87 (d, 1H, J=8.4 Hz.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].CN1CCOCC1>CS(C)=O.C(OCC)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:27][CH2:26][C:25]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1F
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
N-{4-fluoro-3-nitro-phenyl}-benzenesulphonamide (3.0 g, 10 mmol), 3,5-bis-trifluoromethylbenzylamine (3.0 g, 12.5 mmol) and N-methylmorpholine (2.2 mL, 20 mmol) in 25 mL dimethylsulphoxide are kept for 6 h at 60-100° C., diluted with 150 mL ethyl acetate, washed with water, dilute hydrochloric acid and water again, dried and concentrated by evaporation until not quite dry. The residue is combined with 80 mL EtOH and evaporated down to a residual volume of about 50 mL. The crystals precipitated after cooling are filtered off and washed with EtOH and petroleum ether.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20][S:21][CH2:22][CH2:23]Cl.O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH2:23][CH2:22][S:21][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCN(C)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.095 g, 0.32 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.015 g, 0.38 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then chloroethyl methyl sulfide (0.042 g, 0.38 mmol) was added in one portion as a solution in DMF (1 ml) and the reaction mixture was heated to 70° C. for 24 hours. After this time, the reaction mixture was cooled to RT and water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 70% hexane, 30% EtOAc) gave the title compound (0.021 g, 18% yield) as a white solid. δH (400 MHz, CDCl3), 7.73 (1H, d), 7.48 (1H, d), 7.13 (1 H, d), 5.41-5.29 (1H, m), 3.71 (2H, t), 3.18 (3H, s), 3.15 (3H, s), 2.73 (2H, t), 1.41 (6H, d).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([O:8]CC2C=CC=CC=2)=[C:4]([N+:16]([O-])=O)[C:3]1=[O:19].CCO.CN(C=O)C.[ClH:28]>CO.[Pd]>[ClH:28].[NH2:16][C:4]1[C:3](=[O:19])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Cn1ccc(OCc2ccccc2)c([N+](=O)[O-])c1=O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CO
Product: Cn1ccc(O)c(N)c1=O
Yield: 95 %

Procedure:
To the title compound of step 2 (2.00 g, 7.69 mmol, 1.00 Eq) in MeOH (50 mL)/EtOH (50 mL)/DMF (10 mL) was added Pd—C (10%, 0.2 g) under N2. The suspension was purged with H2 three times and hydrogenated under a balloon for 5 h. The catalyst was removed by fitration, and anhydrous HCl in methanol (10 mL, 1.25 M) was added. Concentration left a residue which was treated a second time with HCl in methanol. Evaporation of the volatile components and triturtion with DCM (30 mL)/hexane (30 mL) gave the title compound (1.29 g, 7.30 mmol, yield: 95%) as a pink HCl salt after drying. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.45-8.02 (br, 3H), 7.64 (d, J=7.6 Hz, 1H), 3.27 (d, J=7.6 Hz, 1H), 3.43 (s, 3H). LCMS: 163.0 (M+Na)+
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4]P(O)(O)=O)(=[O:3])[OH:2].[CH3:29]OP(OC)(OC)=O.P(Cl)(Cl)(Cl)=O>C(OCC)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[O:28][CH3:29])([OH:4])([OH:2])=[O:3]
Reactant: COP(=O)(OC)OC
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@@H]1COP(=O)(O)O

Procedure:
In a clean, dry 500 mL round bottom flask equipped with a stirring bar and under a stream of argon slowly add dry and finely powdered 3′-O-Me-Guanosine (1), (6 g, 20 mmol) to a mixture of trimethylphosphate ((OMe)3P) (50 mL) and phosphorous oxychloride (POCl3) (6 mL, 60 mmol) at 0° C. in small portions with continuous stirring under argon. The mixture was kept at 0-4° C. and allowed to stir at least 19 hrs. Diethyl ether (200 mL) was added to extract the excess phosphorous oxychloride and to simultaneously precipitate the 3′-O-methylguanosine-5′-phosphodichloridate, which was then pelleted by centrifugation and dissolved in 100 mL ice-cold 5% NaHCO3 in water. The resulting aqueous solution was adjusted to pH ˜1.5 using 1 N NaOH. After stirring at 0-4° C. for an additional 20 h, the pH was adjusted to 7.0 and the resulting mixture was applied to a column of DEAE Sephadex A25. The column was washed with 5 mM TEAB buffer, pH 7.5 and then eluted with freshly prepared 1M Triethylammonium bicarbonate (TEAB) buffer, pH 7.5. Fractions containing the 3′-O-Me GMP TEA salt (2) were pooled, concentrated to dryness.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH2:14]([C:16]1[N:17]([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:28])[C:19]=2[N:29]=1)[CH3:15]>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:14]([C:16]1[N:17]([CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:28])[C:19]=2[N:29]=1)[CH3:15]
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: Ic1cccs1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.112 g, 0.03 eq.), 2-iodothiophene (3.9 g, 1.1 eq.), triethylamine (1.1 g, 3 eq.), and copper (I) iodide (0.042 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.5 mmol, 1.0 eq.) in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 6 hours at which time analysis by liquid chromatography/mass spectroscopy indicated that the reaction was complete. The reaction mixture was absorbed onto the top of a column of silica gel (30 g) and the column was eluted sequentially with dichloromethane and 3/97 methanol/dichloromethane. The product was recrystallized from 1,2-dichloroethane to provide 0.25 g of 2-ethyl-1-[5-(thien-2-yl)-4-pentynyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, mp 175.0-190.0° C. (dec.). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, J=8.3, 1.0 Hz, 1H), 7.82 (dd, J=8.3, 1.0 Hz, 1H), 7.48 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.24 (m, 3H), 6.99 (dd, J=5.1, 3.6 Hz, 1H), 5.37 (s, 2H), 4.65 (t, J=7.7 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.63 (t, J=6.2 Hz, 2H), 2.23 (m, 2H), 1.49 (t, J=7.4 Hz, 3H); MS (APCI) m/z 361 (M+H)+; Anal. calcd for C21H20N4S.0.03C2H4Cl2: C, 69.88; H, 5.59; N, 15.51. Found: C, 69.59; H, 5.69; N, 15.34.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Fc1cc(Br)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21

Procedure:
6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2one was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene following the procedure of Example 5, as a white solid; mp 182-183° C.; 1H-NMR (DMSO-d6) δ10.36 (s, 1H, D2O exchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5 Hz), 1.69 (s, 6H), 19F-NMR (DMSO-d6) δ−112.46 (m, 1F), MS (CI) m/z 352 ([M+H]+, 78%), 350 ([M+H]+, 75%); Anal. Calc. For C16H13BrFNO2: C, 54.88; H, 3.74; N, 4.00. Found: C, 54.83; H, 3.82; N, 3.95.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a stirred yellow solution of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1 g, 2.61 mmol) in anhydrous toluene (25 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.947 mL, 1.042 mmol). The mixture was cooled to −35° C. and a solution of 1M catechoborane/THF (3.65 mL, 3.65 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15 C and stirred for additional 30 min. and diluted with EtOAc (30 mL) and sat. Na2CO3 (10 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (S)-methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (888 mg, 2.301 mmol, 88% yield) as off-white solid. EE=95.4% 1H NMR (500 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.19 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 5.78 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 3.56 (d, J=2.7 Hz, 1H), 2.89-1.81 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=386.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8]C(OCC1C=CC=CC=1)=O.C1COCC1.[C:40]1([S:50](Cl)(=[O:52])=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>CN(C)C=O.CN(C1C=CN=CC=1)C.[C].[Pd]>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8][S:50]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophan methyl ester (11.3 g), palladium-carbon (5%, 50% wet, 3.0 g) and THF (50 ml) was subjected to catalytic hydrogenation at room temperature and atmospheric pressure. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. The oil was dissolved in N,N-dimethylformamide (50 ml), and 1-naphthalenesulfonyl chloride (5.8 g) and 4-(N,N-dimethylamino)pyridine (DMAP) (3.2 g) were added to the ice-cooling mixture. After stirring at 0° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off to yield N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan methyl ester (9.8 g, 77%) as crystals. Melting point: 172°-174° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:54]=[C:53]([CH3:55])[C:52]([OH:56])=[C:51]([CH3:57])[CH:50]=1>CN(C=O)C.C(O)=O>[OH:56][C:52]1[C:51]([CH3:57])=[CH:50][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:54][C:53]=1[CH3:55]
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: Cc1cc(CN)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (67 mg, 0.30 mmol), TBTU (106 mg, 0.33 mmol) and ethyl-diisopropylamine (169 μL, 0.99 mmol) in DMF (2 mL) is allowed to stand at rt for 10 min. A solution of 4-aminomethyl-2,6-dimethyl-phenol (45 mg, 0.30 mmol) in DMF (0.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL) the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) as a colourless oil. LC-MS: tR=1.03 min, [M+1]+=356.23.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
8.2 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-hydroxyestra-1,3,5(10)-trien-17-one in 86 ml of THF are stirred at RT for 2.5 h with 8.6 ml of 3,4-dihydro-2H-pyran and 820 mg of p-toluenesulphonic acid. 0.5 ml of triethylamine is then added, and the mixture is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 7.8 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-(tetrahydropyran-2-yloxy) oestra-1,3,5(10)-trien-17-one are obtained as a foam.