Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]4[CH:21]=[CH:20][C:19]([Br:38])=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:38][C:19]1[CH:20]=[CH:21][C:22]2[N:23]3[CH:29]=[C:28]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:27](=[O:37])[C:25]4[CH:26]=[C:14]([O:13][CH2:12][C:8]5[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=5)[CH:15]=[C:16]([C:17]=2[CH:18]=1)[C:24]3=4
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2- (5-acetoxymethyl-3-pyridylmethyloxy)-10-bromo-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 24 was suspended in methanol (10 ml), and to the suspension was added an aqueous solution of sodium hydroxide (a solution prepared by dissolving 85 mg of sodium hydroxide in 0.8 ml of water), and the mixture was stirred at room temperature for 1 hour. The crystals precipitated were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (180 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1([NH2:45])[CH2:44][O:43][CH2:42]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:32][C:31]1[C:16]2[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:9]1[CH:8]=[C:4]([C:5](=[O:6])[NH:45][C:41]2([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:42][O:43][CH2:44]2)[CH:3]=[C:2]([F:1])[C:10]=1[CH3:11]
Reactant: NC1(c2ccccn2)COC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)COC4)cc(F)c3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq) and 3-(pyridin-2-yl)oxetan-3-amine 2HCl (0.03 g, 0.134 mmol, 1.2 eq) in DMF at 0° C. was added TEA (0.15 ml, 1.08 mmol, 9 eq) and BOP reagent (0.06 g, 0.136 mmol, 1.2 eq). The reaction mixture was stirred as rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 filtered and the filtrate concentrated. The crude product was purified by preparative HPLC. Yield: 0.010 g (15.3%).
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1[C:9]([OH:11])=[O:10].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:8][C:7]1[C:3]2[CH2:2][O:11][C:9](=[O:10])[C:4]=2[S:5][CH:6]=1
Reactant: Cc1csc(C(=O)O)c1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1csc2c1COC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 50 mL round bottom flask, 3-(Hydroxymethyl)-4-methylthiophene-2-carboxylic acid (440 mg, 2.56 mmol, 1.0 eq) was suspended in dichloromethane (5 mL). To above mixture was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (735 mg, 3.83 mmol, 1.5 eq). The reaction was stirred at r.t. for 18 hr, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. LC-MS (IE, m/z): 155.1 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 7.44 (1H, s), 5.14 (2H, s), 2.24 (3H, s);
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([O:17]C)=[O:16].[I-].[Na+].N1C=CC=CC=1>C(C(C)=O)C.O>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCC(C)=O
Product: O=C(O)c1oc(-c2ccccc2)cc(=O)c1Br

Procedure:
Methyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (587 g) was added to a stirred solution of dry sodium iodide (315 g) in dry methyl ethyl ketone (8 l). The solution was heated under reflux for 5 minutes, then pyridine (152 ml) was added and heating was continued for 31/2 hours. The mixture was cooled, the solid product was dissolved in water (2 l) and the solution was washed with dichloromethane and filtered. The filtrate was diluted to 10 l and acidified with 5 M hydrochloric acid (760 ml) to precipitate the title product (mp 247° C. with decomposition).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])([CH3:3])[CH3:2].C([Li])(CC)C.Cl[C:25]([O:27][CH3:28])=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH3:28][O:27][C:25]([C:10]1[O:9][C:8]([CH3:12])=[C:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17])[CH:11]=1)=[O:26]
Reactant: Cc1occc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10.0 g) in tetrahydrofuran (300 mL) was cooled to −78° C. with stirring was treated drop-wise with sec-butyllithium (3.0 M in cyclohexane, 37 mL). After 1 hour the reaction mixture was treated drop-wise with a solution of methyl chloroformate (5.2 g) in tetrahydrofuran (30 mL) over 10 mins and stirring was continued at −78° C. for 1 hour. The reaction mixture was then treated with saturated ammonium chloride solution (300 mL) and allowed to warm to ambient temperature. The two layers were separated and the organic phase washed with brine (300 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:9 by volume) to give compound 15 as a clear oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10](=[O:45])[CH:11]([NH:37]C(OC(C)(C)C)=O)[CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)[CH2:14]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10](=[O:45])[CH:11]([NH2:37])[CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:22][CH:23]=2)[CH2:14]1
Reactant: COC(=O)C(CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 2-tert-butoxycarbonylamino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester from Example step 8c in methylene chloride at room temperature. After stirring for 1 h, the reaction was concentrated in vacuo to give 2-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester trifluoroacetate salt (0.1 g, 100%) as an oil. MS found: (M+H)+=420.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([CH2:30][CH:31]=[CH2:32])=[CH:20][C:21]4[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([CH2:30][C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:29][C:22]3[O:23][CH2:24][C:25](=[O:28])[N:26]([CH3:27])[C:21]=3[CH:20]=2)[CH2:34][CH2:32]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CCc1cc2c(nc1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc1)OCC(=O)N2C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(CC3CC3)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 50 ml 3 necks round-bottomed flask was tert-butyl(1-(4-(7-allyl-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (52 mg, 0.116 mmol), palladium acetate (32 mg, 0.180 mmol) in diethyl ether (5 ml) to give a yellow solution at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0° C. and trimethylsilyldiazomethane (2 ml) was added via a plastic syringe. The reaction mixture was left stirring at 0° C. for 10 minutes and warmed up to room temperature overnight.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([C:18]([OH:20])=[O:19])[O:10]C1(C)C)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C@H:12]([CH2:13][CH2:14][S:15][CH2:16][CH3:17])[CH:11]([OH:10])[C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19]
Reactant: CCSCC[C@@H]1C(C(=O)O)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSCC[C@@H](N)C(O)C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution of Example 22B (0.102 g, 0.31 mmol), cesium carbonate (0.111 g, 0.34 mmol), and chloromethyl pivalate (0.055 mL, 0.38 mmol) in DMF (3 mL) at room temperature was stirred for 24 hours, diluted with ethyl acetate, washed sequentially with water, aqueous NaHCO3, pH 7 buffer, and brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 4M HCl in dioxane (2 mL), stirred for 1 hour, treated with water (1 mL), stirred for 1 hour, concentrated, and purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 308 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.87–7.80 (br s, 2H), 6.53 (m, 0.7H), 6.33 (d, 0.3H), 4.40 (m, 0.3H), 4.24 (m, 0.7H), 4.28 (s, 0.6H), 4.26 (s, 1.4H), 3.53 (m, 1H), 2.63 (m, 2H), 2.48 (m, 2H), 1.90–1.75 (m, 2H), 1.22–1.16 (m, 12H).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][O-:39].[Na+]>CN(C=O)C>[OH:1][C:2]1([C:29]2[S:33][C:32]([O:39][CH3:38])=[N:31][CH:30]=2)[CH2:3][CH2:4][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) was treated with NaOMe (Aldrich, 0.5 M in MeOH, 1 mL) in DMF (1 mL) at 80° C. for 4 hours. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])=[N:16]2)=[CH:11][CH:10]=1.O>CS(C)=O.C1COCC1.C(OCC)(=O)C>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](/[CH:19]=[CH:20]/[C:21]3[CH:28]=[CH:27][CH:26]=[C:23]([CH:24]4[CH2:2][O:25]4)[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc2ccc(/C=C/c3cccc(C4CO4)c3)nc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of trimethylsulphonium iodide (7.66 g, 37.54 mmol) in dry DMSO (50 ml), under nitrogen was added 50% sodium hydride (1.8 g, 37.54 mmol). The solution was cooled to 10° C. A suspension of 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde 29 (10.0 g, 34.12 mmol) in THF (50 ml) was added to the above solution in one portion. The reaction mixture was stirred at ambient conditions for 2 hours and poured into water (1.0 L) followed by usual work in ethyl acetate, and FC to give the epoxide 30 (7.0 g, 66%) as a cream colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=2)=[N:10]1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C@H:33]2[C:38]([OH:40])=[O:39])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Yield: 60 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.75 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:9]12[CH3:10])[C@@H:22]1[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]1)[CH2:16][CH2:15]3.Cl.O.CCOCC>CO>[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:9]12[CH3:10])[C@@H:22]1[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]1)[CH2:16][CH2:15]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CC[C@@H]2OC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.5 %

Procedure:
To a solution of 0.25 g of 17β-tetrahydropyranyloxy-5α-estr-2-en, Compound 4, in 8 ml of methanol is added 1N hydrochloric acid (0.2 ml) and the reaction mixture is stirred at room temperature for 6 hr. Evaporation of the solvent under vacuum produces a residue of white crystals. The residue is treated with water (15 ml) and ether (25 ml). The ether phase is separated, and the water is extracted once more with 12 ml of ether. The combined ether phase is washed with water, sodium chloride solution, and dried over sodium sulfate. Evaporation of the solvent produces 0.19 g of 17β-hydroxy-5α-estr-2-ene. The structure of the Compound 5, is confirmed by the following spectral data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[I:12].CC(C)([O-])C.[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>C1COCC1>[CH2:10]([C:4]1[C:3]([I:12])=[C:2]([NH:1][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=1)[CH3:11]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCc1cc(N)c(I)c(CC)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc(NCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c(I)c(CC)n1
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
4-amino-2,6-diethyl-3-iodopyridine (2 g) (obtained as described in Example 7 B) was added to a mixture of potassium t-butoxide (0.97 g) and 1,4,7,10,13,16-hexacyclooctadecane (200 mg) in THF (40 ml) and the mixture was stirred for 15 minutes. Compound E (4 g) was added and the mixture was stirred for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in dichloromethane. The solution was washed with 0.1M citric acid solution and dried (MgSO4). Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (12:1 v/v) to give 2,6-diethyl-3-iodo-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (F) (0.9 g) as a solid; NMR (CDCl3): 1.26(d of t, 6H), 2.70(q, 2H), 3.00(q, 2H), 4.35(d, 2H), 5.21(broad t, 1H), 6.10(s, 1H), 6.58(d, 2H), 6.79(d, 2H), 7.04(d, 2H), 7.37(m, 1H), 7.65(m, 2H), 7.86(d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A mixture of 4-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), diisoproylethylamine (0.042 mL, 0.242 mmol) and 4-dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. An additional quantity of 4-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) and 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with 1:1 ethyl acetate hexane. Fractions containing the product were combined and evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (143 mg, 91%). H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.61 (m, 5H), 2.07 (m, 2H), 2.91 (m, 4H), 3.10 (b, 1H), 3.68 (m, 2H), 3.89 (m, 4H), 4.19 (m, 1H), 4.84 (m, 1H), 5.01 (m, 1H), 5.12 (s, 2H), 5.64 (d, 1H), 7.05 (d, 2H), 7.28 (m, 1OH), 7.71 (d, 2H). MS(ESI): 703(M+Na).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CCOC(C)=O.CCN(CC)CC.CN(C)C=O.CC(N(C)C)=O>[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][N:16]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:28])[CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1
Reactant: c1nc2[nH]ncc2c2c1CNCC2
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine trifluoroaceate salt was added benzoic acid (0.064 g, 0.52 mmol), dimethyl acetamide (4 mL), dimethylformamide (2 mL) and Et3N (1.0 mL). The mixture was vortexed to ensure that the solid was fully in solution before adding HBTU (0.20 g, 0.52 mmol). The reaction mixture was shaken at room temperature for 16 hours. On completion of the reaction, EtOAc (20 mL) and 1.5M NaOH (10 mL) was added to the reaction mixture. The organic layer was separated, washed with water (2×20 mL) and concentrated under reduce pressure. The crude product was purified using flash column chromatography (SiO2, 80% EtOAc in hexanes) to give the desired product, (8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)(phenyl)methanone (0.20 g, 15%) as a white solid. M.p.=198-200° C.; 1H NMR (400 MHz, DMSO-d6) δ13.60 (s, 1H), 8.44 & 8.15 (m, 2H), 7.49 (m, 5H), 4.90 & 4.71 (m, 2H), 4.02 & 3.66 (m, 2H), 3.16 (m, 2H); LCMS [M+H]: 279.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.C(N(CC)CC)C>C(#N)C>[O:12]1[CH2:13][CH2:14][N:1]([C@H:2]2[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: BrCCOCCBr
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 60 °C

Procedure:
Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07 g) and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile (20 mL). The reaction mixture was heated at 60° C. overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7%-10% methanol in dichloromethane to give the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH:25]1[O:29][CH2:28][CH2:27][O:26]1)[CH2:15][CH3:16].I[CH2:32][CH3:33]>C1COCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:30])[C:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH:25]1[O:29][CH2:28][CH2:27][O:26]1)([CH2:32][CH3:33])[CH2:15][CH3:16]
Reactant: CCI
Reactant: CCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (60 mL, 60 mmol, 1 M in THF) was slowly added to a solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-butyric acid methyl ester (15 g, 50 mmol) in anhydrous THF (150 mL) at −78° C. After the mixture was stirred for 15 min, iodoethane (9.3 g, 60 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, dried over anhydrous Na2SO4 and concentrated to give the crude product as a oil (16 g).