Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21])#[N:2].[OH-:24].[Na+].Cl>CO>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:24])[NH2:2]
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of 5-(4-Cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (5.25 g, 17.0 mmol) and 1 M NaOH (50 mL) in methanol (150 mL) was stirred at room temperature for 1 h. The mixture was acidified with 6 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate) followed by trituration with diisopropyl ether to give 5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (1.09 g, 19%)
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:8]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][N:24]=2)=[O:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1.COOC(C1C=CC(C(O)=O)=NC=1)=O.O.[OH-].[Li+]>CC(O)=O.O.C1COCC1>[F:1][C:2]1[C:3]([C@@H:8]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=2)=[O:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)cc2)c2ncccc2F)nc1
Agent: COOC(=O)c1ccc(C(=O)O)nc1
Agent: Cl
Agent: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 150 mL round bottom flask containing (S)-methyl 6-(((3-fluoro-pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)nicotinate (250 mg, 0.556 mmol) (prepared using the general coupling procedure Table 2 with Intermediate 1 and 5-((methylperoxy)carbonyl)picolinic acid) were added THF (6 mL) and H2O (2 mL). The resulting mixture was stirred at 23° C. for 2 min. At this time, lithium hydroxide monohydrate (61.8 μL, 2.23 mmol) was added and the reaction was stirred for 3 h. The bulk of the solvent was evaporated to give a foamy solid that oiled out. The residue was dissolved in AcOH (8 mL). The solution was purified by reverse phase HPLC and the product-containing fractions concentrated to give the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 9.65 (d, J=7.3 Hz, 1H), 9.21 (s, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.42 (d, J=7.3 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.63-7.42 (m, 3H), 7.39 (dd, J=4.2, 8.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 6.74 (d, J=6.7 Hz, 1H). MS (ESI pos. ion) m/z: 436.2 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.52-7.67 (m, 2H), 8.12 (ddd, J=8.7, 4.3, 1.5 Hz, 1H), 8.19 (ddd, J=10.8, 7.5, 2.0 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.29 (dd, J=2.0, 0.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:15])([F:14])[C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.CCN(C(C)C)C(C)C>CO>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH:24][C:9](=[O:11])[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([F:14])[F:15])=[N:21][CH:22]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(Cl)nn1
Reactant: NNc1ccc(Br)cn1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(Br)cn1)C(F)(F)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetate (10.8 g, 45.6 mmol) and 5-bromo-2-hydrazinylpyridine (8.58 g, 45.6 mmol) in anhydrous MeOH (100 mL) was added DIEA (5.90 g, 45.6 mmol). The reaction was stirred at ambient temperature for 18 hrs. The solvent was removed via rotary evaporation and the resulting material was reconstituted in EtOAc. The organic phase was washed with water and concentrated to dryness. The resulting residue was purified by MPLC (EtOAc) to provide the title compound, N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)-2,2-difluoroacetohydrazide 45E (13.3 g, 35.1 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (d, J=8.84 Hz, 1 H) 7.11 (d, J=9.35 Hz, 1 H) 7.47-7.60 (m, 2 H) 8.06 (d, J=2.53 Hz, 1 H). ESI-MS:m/z 377.9 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([N:16]1[C:20]2=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:22]=[N:23][CH:24]=[C:19]2[C:18]([CH3:34])=[C:17]1[CH3:35])[CH:13]=[CH:14][CH3:15]>ClCCl>[CH2:12]([N:16]1[C:20]2=[C:21]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:22]=[N+:23]([O-:6])[CH:24]=[C:19]2[C:18]([CH3:34])=[C:17]1[CH3:35])[CH:13]=[CH:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Solvent: ClCCl
Product: CC=CCn1c(C)c(C)c2c[n+]([O-])nc(OCc3ccc(F)cc3)c21
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A solution of 0.72 g (0.0029 mole) of m-chloroperoxybenzoic acid (purity: 700%) in 20 ml of dichloromethane was added to a solution of 0.72 g (0.0029 mole) of 1-(2-butenyl)-7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine in 70 ml of dichloromethane at room temperature and the resulting mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was washed three times with 40 ml each of a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 100:1 to 100:4 mixture of chloroform and methanol as an eluent to give crystals, which were washed with a mixture of ether and hexane to give 0.63 g of the title compound (cis/trans=27/73) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:31])[CH3:30])=[CH:24][C:23]=1[O:32][CH3:33]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:31])[CH3:30])=[CH:24][C:23]=4[O:32][CH3:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Solvent: CC#N
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO2 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:25][CH2:24][CH2:23][C@@:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[N:6][CH:7]=1.O1CCOCC1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[OH:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]2[CH2:12][CH2:11][C@:10]3([CH2:23][CH2:24][CH2:25][N:8]([C:5]4[N:4]=[CH:3][C:2]([N:32]5[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:7][N:6]=4)[CH2:9]3)[C:14]2=[O:15])[CH2:17][CH2:18]1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ncc(Br)cn1)C2
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ncc(-n3cccn3)cn1)C2
Temperature: 150 °C
Reaction time: 16 h

Procedure:
To a solution of (5S)-7-(5-bromopyrimidin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (30 mg, 0.00007 mol, this compound was prepared by using procedures that were analogous to those described for the synthesis of example 420) in 1,4-dioxane (1 mL, 0.01 mol) was added 1H-pyrazole (6.0 mg, 0.0000880 mol), (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (2.3 μL, 0.000015 mol), copper(I) iodide (1.4 mg, 0.0000073 mol), and potassium carbonate (0.0213 g, 0.000154 mol). After stirring at 150° C. for 16 h, the reaction mixture was filtered and purified by prep-HPLC to afford the desired product. LC-MS: 397.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:31]([N:35]1[CH:39]=[CH:38][C:37](I)=[N:36]1)([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].N#N>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(Cl)Cl.COCCOC>[C:31]([N:35]1[CH:39]=[CH:38][C:37]([C:11]2[CH:10]=[C:9]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:8]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[N:6][C:7]=3[CH:12]=2)=[N:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)n1ccc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccn(C(C)(C)C)n2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 60.2 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 1-(tert-butyl)-3-iodo-1H-pyrazole (145.9 mg, 0.584 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give yellow solids, 71.6 mg (yield 60.2%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.59 (broad s, 2H), 7.27 (s, 1H), 6.71 (d, J=2.3 Hz, 1H), 4.78 (p, J=5.9 Hz, 1H), 3.70 (m, 1H), 3.46-3.35 (m, 1H), 3.21 (m, 1H), 2.88-2.72 (m, 1H), 2.41-2.25 (m, 2H), 1.57 (s, 9H), 1.32 (d, J=5.9 Hz, 3H), 1.14-1.06 (m, 2H), 1.06-0.95 (m, 2H) ppm; MS (ESI+) m/z 408 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([O:11][CH:12]1[C:13]([O:55][CH:56]([O:58][CH2:59][CH3:60])[CH3:57])([CH3:54])[CH2:14][CH2:15][CH:16]([O:48][CH:49]([O:51][CH2:52][CH3:53])[CH3:50])[CH2:17][C:18]([O:20][CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[CH:22]([CH3:25])[CH:23]=[CH:24]1)=[O:19])=[O:10].C(OCC)(=O)C.O>CN(C)C=O>[CH2:52]([O:51][CH:49]([O:48][CH:16]1[CH2:15][CH2:14][C:13]([O:55][CH:56]([O:58][CH2:59][CH3:60])[CH3:57])([CH3:54])[CH:12]([O:11][C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:24]=[CH:23][CH:22]([CH3:25])[CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[O:20][C:18](=[O:19])[CH2:17]1)[CH3:50])[CH3:53]
Reactant: C1COCCN1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CCl)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Morpholine (9 mg, 0.103 mmol) was added to a solution of (8E,12E,14E)-7-chloroacetoxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (8.1 mg, 10.3 μmol) in N,N-dimethylformamide (1 mL) at room temperature, followed by stirring at 60° C. for one hour. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane=1:2 and 1:1, successively) to obtain the title compound (7.3 mg, 85%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=[N:10]O)[CH2:2][CH2:3][CH3:4].[ClH:26]>C(O)(=O)C>[ClH:26].[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C=NO)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime (3.6 g), stannous chloride dihydrate (12 g), concentrated hydrochloric acid (25 ml) and acetic acid (50 ml) is heated on a steam-bath for 2-3 hours. After concentration in vacuo to about 50 ml, 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine hydrochloride starts to crystallize from the solution. After cooling, the hydrochloride is collected by filtration, washed with ethanol and dried in air. After recrystallization from 2-methoxyethanol it is obtained with a melting point higher than 300° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][CH:11]1[C:34]([OH:36])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[F:70][C:71]1[CH:72]=[C:73]([CH:76]=[CH:77][CH:78]=1)[NH:74][CH3:75]>C1COCC1>[F:70][C:71]1[CH:72]=[C:73]([N:74]([CH3:75])[C:34]([CH:11]2[C@H:10]([OH:9])[C@H:14]([OH:15])[C@@H:13]([CH2:24][OH:25])[O:12]2)=[O:36])[CH:76]=[CH:77][CH:78]=1
Reactant: O=C(OC[C@H]1OC(C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CNc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: CN(C(=O)C1O[C@H](CO)[C@@H](O)[C@H]1O)c1cccc(F)c1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
(3R,4R,5R)-3,4-Bis(benzoyloxy)-5-(benzoyloxymethyl)tetrahydrofuran-2-carboxylic acid (3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid, 2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon atmosphere. To this, triphenylphosphine (2.1 g, 8 mmol) was added and the mixture was stirred until it was dissolved completely. To this clear solution, 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added and the mixture was stirred at room temperature for 2 hours, after which, 3-fluoro-N-methylaniline (0.7 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 ml), the solution washed twice with 0.1M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL), and then dried over Na2SO4. The solution was evaporated to dryness and the residue was re-dissolved in methanolic ammonia (7M solution, 250 mL). The solution was stirred for 16 hours at room temperature and evaporated to dryness. The crude product was purified by silica gel chromatography using a mixture of chloroform-methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as a colorless oil (0.5 g, 1.7 mmol, 42%): MS (ES) m/z 308 [M+Na]+, 284 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C(CCCC1CCCCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCC1CCCCCCC1)C(=O)OCC

Procedure:
5.5 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester, in the form of an oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 10.1 g of (3-cyclooctylpropyl)-malonic acid ethyl ester, 1.28 g of paraformaldehyde, 10 ml of pyridine and 0.5 ml of piperidine.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(Cl)Cl>[CH2:30]([O:29][C:27]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH3:18])=[O:16])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 64.1 %

Procedure:
A solution of 257A (447 mg, 1.7 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.3 mL, 2.2 mmol) followed by benzyl chloroformate (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was stirred for 18 hours, then washed with water (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL) and the combine organics were washed with saturated aqueous NaHCO3, 0.1N HCl, and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to an oil. The crude material was purified by flash chromatography (30% EtOAc/hexanes) on silica gel to afford 411 mg (yield: 75%) of Compound 257B as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][CH2:29][C@H:30]1[CH2:35][N:34]([C:36]2[CH:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=2)[CH2:33][CH2:32][N:31]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>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.[Pd].[Pd].O1CCOCC1>[Si:21]([O:28][CH2:29][C@H:30]1[CH2:35][N:34]([C:36]2[CH:37]=[N:38][C:39]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[CH:40][CH:41]=2)[CH2:33][CH2:32][N:31]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Yield: 68.6 %

Procedure:
A 10 mL reaction vessel was charged with compound 245 (83.0 mg, 306 μmol), compound 309 (135 mg, 306 μmol), tris(dibenzylideneacetone)dipalladium (0) (21.0 mg, 22.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (26.6 mg, 45.9 μmol), sodium t-butoxide (58.8 mg, 612 μmol), and dioxane (2.5 mL). The reaction was purged with argon and heated with microwave energy (300 W) for 2 hours at 120° C. The resulting solution was added to aqueous K2CO3 (30 mL) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Silica gel chromatography (gradient elution hexanes/20-100% ethyl acetate) afforded compound 310 as a colorless oil (142 mg, 69%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=[O:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[CH3:26]C(C)([O-])C.[K+].O>CI.C(O)(C)(C)C>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=[O:23])[C@@:20]4([CH3:26])[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C3OCCOC3C[C@@H]12
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Solvent: O
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3CC4OCCOC4[C@@]3(C)CC(=O)[C@]21C
Reaction time: 18 h

Procedure:
To a stirred, ice cooled solution of 10.5 g of 17-ethylenedioxy-3-methoxyestra-1,3,5(10)-trien-11-one in 300 ml of methyl iodide under an atmosphere of nitrogen is added, over 10 minutes, 120 ml of a 1.1 molar solution of potassium tert.-butoxide in t-butyl alcohol. The temperature is allowed to rise to room temperature and the mixture is then stirred for 18 hours. It is next poured onto 500 ml of water and extracted with methylene chloride, twice. The combined organic extracts are washed with water and dried over sodium sulfate. Removal of the solvent gives an oil which is crystallized from ether to yield 17-ethylenedioxy-3-methoxy-9α-methylestra-1,3,5(10)-trien-11-one, m.p. 142° - 145° C.