Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)=[O:10].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH2:37][CH2:38]I)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]([N:11]1[CH2:18][CH:17]2[CH2:16][N:15]([CH2:38][CH2:37][CH2:36][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][CH:13]2[CH2:12]1)=[O:10]
Reactant: O=S(=O)(c1ccccc1)N(CCCI)c1ccc(F)cc1
Reactant: Cc1cccc(C)c1C(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)N1CC2CN(CCCN(c3ccc(F)cc3)S(=O)(=O)c3ccccc3)CC2C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 66 (0.012 g, 0.05 mmol) in MeCN (1 mL) at RT were added N-(4-fluoro-phenyl)-N-(3-iodo-propyl)-benzenesulfonamide (102, 0.025 g, 0.06 mmol) and K2CO3 (0.01 g, 0.075 mmol). The reaction mixture was shaken at 80° C. for 48 h. After cooling to RT, the mixture was diluted with DCM (5 mL), filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to afford II-2: MS (ES+) m/z=536 (M+H)+.
Reaction SMILES: [ClH:1].Cl.N[C@H]1CCN([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)C1.OC1(C(C2C=CC=C(OC(F)(F)F)C=2)C([N:39]2[CH2:43][CH2:42][C@H:41]([NH:44]C(=O)OC(C)(C)C)[CH2:40]2)=O)CCCCC1>>[ClH:1].[ClH:1].[NH2:44][C@H:41]1[CH2:42][CH2:43][N:39]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]2([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH3:9])[OH:28])[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: N[C@H]1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CC(c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1N1CC[C@H](N)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl ((3S)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}pyrrolidin-3-yl)carbamate MS (ESI) m/z 373; HRMS: calcd for C19H27F3N2O2+H, 373.21029; found (ESI, [M+H]+), 373.2106.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[O-:10])[CH:5]=[N:6][CH:7]=1>C(O)(=O)C.[Rh].[Pt](=O)=O>[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:10])[O:11][C:2]([CH3:3])([CH3:7])[CH3:1])[CH2:3]1
Reactant: Cc1cncc(NC(=O)[O-])c1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
To a solution of 5-methylpyridin-3-ylcarbamate (3 g, 14 mmol) in glacial acetic Acid (50 mL) was added 5% Rhodium on active carbon (0.5 g) and Platinum(IV) oxide (0.5 g) in the hydrogenation steel bomb. The mixture was sealed and hydrogenated at 200 psi and 70° C. for 48 h. the mixture was filtered through Celite and concentrated to give cis-(+/−)-tert-butyl 5-methylpiperidin-3-ylcarbamate. LCMS (m/z): 215.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(N)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].IC.[CH3:22][N:23]([CH:25]=O)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:25]([N:23]([CH3:22])[CH3:24])[C:10]2[C:11]([CH:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COc1cc(N)c2ccccc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc(N(C)C)c2ccccc2c1
Reaction time: 24 h

Procedure:
To a solution of 3-methoxy-1-aminonaphthalene (U.S. Pat. No. 7,018,431 B2, 0.13 g) in DMF (5 mL), K2CO3 (0.31 g) and iodomethane (0.09 mL) were added. After stirring for 24 hours, the reaction was partitioned between water (30 mL) and EtOAc (30 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated. The crude reaction purified over silica gel (gradient of EtOAc in heptane) to provide the title compound (0.14 g) as a clear oil: 1H NMR (DMSO-d6) δ 7.99 (d, 1H); 7.74 (d, 1H), 7.40 (ddd, 1H), 7.30 (ddd, 1H), 6.95 (d, 1H), 6.67 (d, 1H), 3.83 (s, 3H), 2.78 (s, 6H); MS expected 202 (C13H16NO, M+1), found 202.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:29]([C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[N:4][C:3]([C:2]([F:15])([F:16])[F:1])=[N:5]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)cc2)cc1
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (0.92 g, 3.95 mmol) in 10 mL of dioxane, were added pyridine (0.319 mL, 3.95 mmol) and a solution of 4-methoxybenzoyl chloride (673 mg, 3.95 mmol) in 3 mL of dioxane. The mixture was refluxed with stirring for 12 hours. The solvent was removed under reduced pressure. 50 mL of dichloromethane and 20 mL of 0.1 N hydrochloric acid were added to the residue and the organic layer was separated. The aqueous layer was extracted with 50 mL of dichloromethane. A combined organic layer was washed with 0.1 N hydrochloric acid and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (toluene-ethyl acetate 9:1) and then recrystallized with diisopropyl ether-hexane to give pale brown needle of 1,5-bis(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (0.67 g, 48.6% yield).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][CH:21]=2)=[N:10]3)[CH2:6][CH2:5]1)([OH:3])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[NH:25])=[CH:28][CH:29]=2)=[N:10]3)[CH2:6][CH2:5]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: Cn1c(=O)c(Cc2ccc(C(=N)NO)cc2)nc2cc(C3(C(=O)O)CC3)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)c(Cc2ccc(C(=N)N)cc2)nc2cc(C3(C(=O)O)CC3)ccc21

Procedure:
300 mg (0.76 mmol) of 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-hydroxybenzamidine are dissolved in 30 ml of 90% acetic acid and after the addition of 400 mg palladium on activated charcoal hydrogenated with hydrogen at 60° C. The catalyst is filtered off, the solution is evaporated down. The residue is chromatographed on silica gel and eluted with methanol. The desired fractions are evaporated down, triturated with ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>CO>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CC=C(c2ccc(N)c(C(F)(F)F)c2)CC1
Solvent: CO
Product: CCCN1CCC(c2ccc(N)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(1-Propyl-1,2,3,6-tetrahydropyridine-4-yl)-2-trifluoromethyl-phenylamine, the titled compound was recovered by the procedure described in Preparation 6: MS m/z (rel. intensity, 70 eV)) 286 (M+, 2), 257 (17), 98 (10), 96 (8), 70 (bp), Rf=0.28 (MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([NH2:38])[CH:32]=1>>[NH2:38][C:33]1[CH:32]=[C:31]([O:30][CH3:29])[CH:36]=[CH:35][C:34]=1[NH:37][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc(NC(=O)c2cccc3cc(Oc4ncnc5cc(OC)c(OC)cc45)ccc23)c(N)c1
Yield: 87 %

Procedure:
The title compound (43.2 mg, 87% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-methoxy-o-phenylenediamine (16.5 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.70 (s, 3H, —OCH3), 4.01 (s, 6H, 2×OCH3), 5.00 (s, 2H, benzene-NH2), 6.23 (dd, J=2.6 and 8.6 Hz, 1H, Ar—H), 6.40 (d, J=2.6 Hz, 1H, Ar—H), 7.22 (d, J=8.6 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.59 (dd, J=2.2 and 9.1 Hz, 1H, Ar—H), 7.62-7.66 (m, 2H, Ar—H), 7.86 (d, J=6.9 Hz, 1H, Ar—H), 7.96 (d, J=2.0 Hz, 1H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.70 (s, 1H, benzene-NH). LC-MS (m/z) 497 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(OC(=O)C)(=O)C>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C=Cc2ccncc2)cc1
Yield: 54.9 %

Procedure:
The photo-bleachable compound expressed by the structural formula (II-14) was prepared in the following manner. Thus, a reaction mixture was prepared by dissolving 6.81 g (0.05 mole) of p-anisaldehyde and 4.66 g (0.05 mole) of γ-picoline in 10.21 g (0.10 mole) of acetic anhydride and the mixture was heated under reflux for 16 hours to effect the reaction. After acetic acid and the unreacted acetic anhydride were evaporated from the reaction mixture, the residual reaction mixture was poured into water so that a crystalline material was precipitated therein. The reaction mixture was filtered and the collected precipitates were washed with water. Recrystallization of the precipitates from a mixture of methyl alcohol and water gave 5.80 g of 4-[2-(4-methoxyphenyl)ethenyl]pyridine, the yield of which was 55% of the theoretical value.
Reaction SMILES: [Br:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[Cl:11][SiH:12]([CH3:14])[CH3:13]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[Br:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH:6]([Si:12]([Cl:11])([CH3:14])[CH3:13])[CH2:7][CH3:8])=[O:4]
Reactant: C=CCOC(=O)C(C)(C)Br
Reactant: C[SiH](C)Cl
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCC(OC(=O)C(C)(C)Br)[Si](C)(C)Cl
Reaction time: 72 h

Procedure:
To a round-bottomed flask, allyl 2-bromo-2-methylpropionate (2.5 mL) was mixed with dry toluene (30 mL) under nitrogen flow. Chlorodimethylsilane (12.2 mL) was added dropwise to the flask and subsequently Platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (solution in xylene, Pt˜2%, 0.3 mL). The mixture was stirred under nitrogen for 3 days, after which the mixture was stripped under vacuum to remove toluene and unreacted chlorodimethylsilane. The product, 1-(chlorodimethylsilyl)propyl 2-bromoisobutyrate, was obtained as a yellow oil. 1.6 mL of this oil was then added via syringe to a silica/MEK (Methyl Ethyl Ketone) suspension (Nissan, 30 wt % suspended in MEK, particle size of SiO2˜15-20 nm, 13 g) in a round-bottomed flask under nitrogen flow. The mixture was stirred for 24 hours at 50° C., after which the mixture was cooled down and hexamethyldisilazane (1.5 mL) was added. The mixture was stirred at room temperature for 3 hours and heated to 40° C. for overnight, after which the mixture was cooled down. The precipitate was removed by centrifugation (5000 rpm for 0.5 hours), and the supernatant was added dropwise into hexane to precipitate colloids. The particles were washed with hexanes for several times and dried under vacuum. Solution NMR of the silica-bound initiator (Br-silica) showed no peaks for 1-(chlorodimethylsilyl)propyl 2-bromoisobutyrate or allyl 2-bromo-2-methylpropionate indicating that all free initiator was gone.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromopyridine
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccc(OC)nc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(-c3ccc(OC)nc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 55 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6′-methoxy-N-(6-methoxypyridin-3-yl)-3,3′-bipyridin-6-amine (0.163 g, 0.249 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature, the mixture was concentrated, the crude residue was treated with 2M NH3 in MeOH and dry-packed with silica gel. Purification using an ISCO Combiflash Companion (40 g column; 1-20% MeOH in DCM over 25 min; product eluted with 10% MeOH) afforded 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6′-methoxy-N-(6-methoxypyridin-3-yl)-3,3′-bipyridin-6-amine (0.0572 g, 0.137 mmol, 55.2% yield) as an orange colored amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.81 (s, 1H); 8.98 (d, J=2.7 Hz, 1H); 8.62 (d, J=2.5 Hz, 1H); 8.56 (d, J=2.7 Hz, 1H); 8.47 (d, J=2.3 Hz, 1H); 8.20 (dd, J=8.8, 2.7 Hz, 1H); 8.00 (dd, J=8.6, 2.7 Hz, 1H); 7.90 (br. s., 1H); 7.76 (br. s., 1H); 6.94 (d, J=8.6 Hz, 1H); 6.85 (d, J=8.8 Hz, 1H); 3.90 (s, 3H); 3.86 (s, 3H); 2.46 (s, 3H). m/z (ESI, +ve ion) 417.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][O:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:17]>CO>[ClH:17].[O:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2C1
Agent: Cl
Solvent: CO
Product: c1cc2c(o1)CNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5.324 g (23.85 mmol) of 6-tert-butoxycarbonyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 100 ml of methanol, 5 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure to yield the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]3[O:17][C@@:18]45[CH2:28][CH2:27][C@H:26]([OH:29])[C:25]([CH3:31])([CH3:30])[C@@H:24]4[CH2:23][CH2:22][C@H:21]([CH3:32])[C@@:19]5([CH3:33])[CH2:20][C:13]=3[C:12]([O:34][P:35]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:36])=[CH:11][C:10]=2[C:9]1=[O:51])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:29][C@@H:26]1[C:25]([CH3:31])([CH3:30])[C@H:24]2[C@@:18]3([O:17][C:14]4[C:15]5[CH2:16][NH:8][C:9](=[O:51])[C:10]=5[CH:11]=[C:12]([O:34][P:35]([O:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([O:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:36])[C:13]=4[CH2:20][C@:19]3([CH3:33])[C@@H:21]([CH3:32])[CH2:22][CH2:23]2)[CH2:28][CH2:27]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OP(=O)(Oc4ccccc4)Oc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OP(=O)(Oc4ccccc4)Oc4ccccc4)cc4c2CNC4=O)C[C@]13C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a solution of the above Compound (56a) (256 mg, 0.36 mmol) in 2.5 ml of dry dichloromethane were added 50 μl of anisole and 2.5 ml of trifluoroacetic acid, and the mixture stirred for 10 min at the same temperature, and then for one hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was made basic with 7% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (silica gel 15 g; ethyl acetate) to give 203 mg (91%) of Compound (57a).
Reaction SMILES: [C:1]([C:3](O)([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4])#[N:2].CC([C@@H]1[C@@]2(C)CC[C@@H]3[C@]4(C)C(=CC(CC4)=O)CC[C@H]3[C@@H]2CC1)=O.CS(Cl)(=O)=O.N1C=CC=CC=1>CC(C)(O)C#N.C(N(CC)CC)C.O>[C:1]([C:3](=[C:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4])#[N:2]
Reactant: CC(O)(C#N)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(O)C#N
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C#N)=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
The procedure of Ercoli and Ruggieri (Gazz. Chim. Ital. 84, 312, 1954, incorporated herein by reference) was followed to prepare 20-cyano-20-hydroxy-4-pregnene-3-one (I-25) from progesterone. Thus, the suspension of progesterone 1.2 g in acetone cyanohydrin 2.4 ml was stirred and warmed at 40° C. until all the progesterone was dissolved. Four drops of triethylamine was then added. After 2 h the precipitate was filtered and dried to give crude I-25 1.4 g; m.p. 188°-90° C. After recrystallization from ethanol (contained 1% acetic acid), the product was obtained as fine crystals, m.p. 199°-200° C. The mixture containing cyanohydrin (I-25) 0.4 g, methane sulfonyl chloride 1 ml and pyridine 5 ml was stirred at room temperature for 5 h, then at 80° C. for 1 h. Water 20 ml was added and the precipitate was collected. The crude product was chromatographed on silica gel TLC plate (developed by hexane:/ethyl acetate, 1:1). The yield of I-26 was 80 mg, m.p. 195°-6° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([C:15]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23](=[O:35])[C:22]3=[O:36])[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:11]>O1CCCC1>[C:31]([O:30][C:28]([NH:24][C:25]1[CH:26]=[CH:27][C:19]([C:15]2([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17][CH2:18]2)=[CH:20][C:21]=1[C:22](=[O:36])[C:23]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:35])=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3C(=O)OC(C)(C)C)CCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
1.049 g of isoindoline are added to 3.3 g of 5-(1-ethoxycarbonylcyclobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 1.2 g (28%) of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylate; LC-MS retention time: 2.75 min (“nonpolar” gradient).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([O:5]CC)=[O:4].[CH3:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:17][CH3:18]>>[CH3:15][CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=[O:4])=[CH:23][CH:24]=1)[CH2:17][CH3:18]
Reactant: CCCCCCCC(Br)C(=O)OCC
Reactant: CCC(C)c1ccc(O)cc1
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O

Procedure:
By use of the procedures described in Examples 1 and 3, ethyl 2-bromononanoate and 4-(1-methylpropyl )phenol were coupled and the product saponified to give 2- (4-(1-methylpropyl)phenoxy)nonanoic acid. This material (1.0 g) was then methylated at the 2-position according to the procedure of Pfeffer, et. al. (J. Org. Chem., 1972, 37, 451) to give 2-methyl-2-hexanethiodecanoic acid (0.928 g). This material (0.86 g) was converted to the corresponding acid chloride with oxalyl chloride and coupled with 2,4,6-trimethoxyaniline (0.49 g) according to the procedure of Adams and Ulrich (J. Am. Chem. Soc., 1920, 42, 599) to give the title compound (1.12 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[O:24]=[C:22]([NH:32][O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)/[CH:21]=[CH:20]/[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[N:19][CH:18]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
A mixture of (2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (450 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (174 mg), HOBt (191 mg) and EDCI (220 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (450 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[CH2:30]([OH:33])[CH2:31][OH:32]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:32][CH2:31][CH2:30][OH:33])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)c1cccc(COCCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 52 %

Procedure:
Following a procedure similar to that described in Preparation 1(ii), but using N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28(iv)] and ethylene glycol as starting materials, in relative amounts similar to those used in that Preparation, the title compound, melting at 153°-154° C. (after recrystallization from a mixture of diethyl ether and hexane), was obtained in a 52% yield.