Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]([F:36])([F:35])[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:27]3[C:26]([C:25]([F:36])([F:24])[F:35])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ncccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3C(F)(F)F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3-trifluoromethyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=397.0 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][O:14][P:15]([CH:21]([OH:42])[C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH:27]([C:36]([O:38][CH3:39])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:24][CH:23]=1)([O:17][O:18][CH2:19][CH3:20])=[O:16])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:19]([O:18][O:17][P:15]([C:21](=[O:42])[C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH:27]([C:36]([O:38][CH3:39])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[CH:24][CH:23]=1)([O:14][O:13][CH2:11][CH3:12])=[O:16])[CH3:20]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOOP(=O)(OOCC)C(=O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
To a solution of oxalyl chloride (371 μL, 548 mg, 4.32 mmol, 2 equivalents) in anhydrous CH2Cl2 (8 mL) at -78° C. under argon was added anhydrous DMSO (612 μL, 674 mg, 8.64 mmol, 4 equivalents) in anhydrous CH2Cl2 (8 mL) dropwise over 17 minutes. To the resulting clear, colorless solution was added 40 (961 mg, 2.16 mmol) in anhydrous CH2Cl2 (8 mL) dropwise at -78° C. over 15 minutes. The reaction was stirred at -78° C. (45 minutes) then NEt3 (3.00 mL, 2.18 g, 21.6 mmol, 10 equivalents) in anhydrous CH2Cl2 (8 mL) was added dropwise at -78° C. over 10 minutes. The resulting clear, light yellow solution was stirred at 0° C. (50 minutes), then shaken well with ice-cold 0.2 N HCl/brine (100 mL); extracted with EtOAc (3×75 mL); washed with ice-cold 0.2 N HCl/brine (2×50 mL); brine (2×100 mL); dried (MgSO4) and rotovapped (20° C.) once from CHCl3, then twice from CH2Cl2 and placed under high vacuum, yielding 41 as an oil (962 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:15]
Reactant: Cc1nccn1-c1ccc(I)cc1
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(Oc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 130 °C
Yield: 38.3 %

Procedure:
A mixture of 4-(2-methylimidazol-1-yl)phenyl iodide (1.28 g, 4.5 mmol), 4-cyano-4-(3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (1.20 g, 5.9 mmol) and K2CO3 (4.15 g, 30 mmol) in pyridine (50 ml) was heated at 130° C., cupric oxide (636 mg, 8.0 mmol) added and the reaction mixture was heated under reflux for 2 days. The reaction mixture was cooled and filtered through a celite pad and the solids were washed with ethyl acetate (100 ml). The filtrate was concentrated in vacuo, and the resulting residue was diluted with water (100 ml) and extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with 1 N aqueous NaOH (100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography {LiChroprep NH2 (Merck), 100 g; eluted with hexane/ethyl acetate (1/1)} to afford 620 mg (38%) of the titled compound as a yellow oil.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[CH:13][CH:12]=1)=[O:8])[CH3:11]
Reactant: Clc1ccc(OCCCCCCCBr)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCCCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium (2.5 g., 0.11 M) was dissolved in absolute ethanol (50 ml) and ethyl 4-hydroxybenzoate (16.6 g., 0.10 M) in ethanol (50 ml) was added at room temperature. The mixture was stirred at room temperature for 15 min, 1-bromo-7-(4-chlorophenoxy)-heptane (0.10 M) in ethanol (50 ml) was added in one portion and the mixture was boiled under reflux with stirring for 24 hours. The hot solution was filtered to remove sodium bromide, the ethanol removed under vacuum, the product dissolved in dichloromethane (100 ml) and washed with 5% sodium hydroxide solution (2×100 ml) and water (2×100 ml). The dichloromethane solution was dried (MgSO4), filtered, evaporated and the product purified by crystallisation, from ethanol m.p. 70°-71°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:14]O>>[CH:1]1([C:4]2[C:5]([C:10]([O:12][CH3:14])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(O)c1ncccc1C1CC1
Agent: Cl
Product: COC(=O)c1ncccc1C1CC1

Procedure:
830 mg of a hydrochloride salt of the 3-cyclopropylpyridine-2-carboxylic acid [121-3] was dissolved in 100 mL of 10% hydrochloric acid-methanol solution, and heated overnight under reflux. The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the obtained residue, and was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 363 mg of methyl 3-cyclopropylpyridine-2-carboxylate [121-4] was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)[C:5](=[O:31])[C:4]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:43])([CH3:42])[CH2:36][CH:35]2[OH:44])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH3:43][C:37]1([CH3:42])[CH2:36][C:35](=[O:44])[C:34]2[C:39](=[CH:40][CH:41]=[C:32]([C:4]3[C:5](=[O:31])[N:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:25]5[NH:29][C:28](=[O:30])[O:27][N:26]=5)=[CH:15][CH:14]=4)[C:7]([CH2:9][CH2:10][CH3:11])=[N:8][C:3]=3[CH2:1][CH3:2])[CH:33]=2)[O:38]1
Reactant: CCCc1nc(CC)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 6-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one (0.78 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.84 g) in dichloromethane (8 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 81%).
Reaction SMILES: C(OC([N:8](C)[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH:14]1([CH2:13][C@@H:9]([C:10]([NH:36][C@@H:33]2[C@@H:31]3[C@@H:30]([CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:37])[F:38])=[CH:27][CH:26]=4)[CH2:32]3)[CH2:35][CH2:34]2)=[O:12])[NH2:8])[CH2:16][CH2:17]1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: N[C@@H](CC1CC1)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 3-cyclopropyl-N-(tert-butoxycarbonyl)-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.33 (d, J=7.6, 1H), 7.20-7.18 (m, 2H), 6.62-6.54 (m, 2H), 4.40-4.32 (m, 1H), 3.71 (dd, J=7.4, 5.3, 1H), 3.52 (dd, J=9.9, 3.0, 1H), 3.24 (dd, J=9.8, 7.6, 1H), 3.13 (dd, J=9.6, 7.8, 1H), 3.00 (dd, J=9.6, 3.6, 1H), 2.77-2.60 (m, 2H), 2.33 (s, 2H), 2.08 (dt, J=12.2, 6.7, 1H), 1.99-1.83 (m, 2H), 1.73 (dt, J=13.9, 7.1, 1H), 1.63 (ddd, J=16.0, 12.4, 7.7, 1H), 1.37 (td, J=12.8, 7.1, 1H), 0.94 (dt, J=12.1, 4.9, 1H), 0.52-0.37 (m, 2H), 0.21-0.07 (m, 2H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(=O)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (4.694 g, 21 mmol) was reacted with heptanophenone (3.806 g, 20 mmol) in ethanol (60 ml) to give the product (5.681 g, 16.598 mmol, 79%) as an oily solid. 1H NMR (DMSO-d6) δ 0.79 (t, J=6.8 Hz, 3H), 1.19-1.31 (m, 4H), 1.51-1.57 (m, 2H), 2.75 (t, J=7.8 Hz, 2H), 7.15 (dd, J=2.0, 8.5 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.55-7.58 (m, 2H), 7.64 (d, J=1.8 Hz, 1H), 11.29 (s, 1H); [ESI(−)], m/z 340/342 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[O-:13][CH2:14][CH3:15].[Na+].C(O)C.O.Cl>C(O)C>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:13][CH2:14][CH3:15])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: CC[O-]
Reactant: COC(=O)c1cc(Br)oc1CBr
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCc1oc(Br)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (4.5 g) in ethanol (50 mL) was added 20% sodium ethoxide-ethanol solution (7.8 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr and at room temperature overnight. The reaction was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (2.8 g, 67%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]2[CH2:25][CH3:26])=[CH:17][C:16]=1[F:31]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[CH:7]1[NH:8][CH2:9][CH2:10][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]3[CH2:25][CH3:26])=[CH:17][C:16]=2[F:31])[CH2:12]1
Reactant: Clc1cc(C2CNCCN2)c(Cl)s1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(Cl)sc4Cl)C3)cc21

Procedure:
A 3.1 g portion of 2-(2,5-dichloro-3-thienyl)piperazine was dissolved in 8 ml of pyridine, 880 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated, under argon, in a pressure bottle, at 120°-130° C. for 18 hours. After cooling, the solid was collected, washed with ethanol, dried and recrystallized from dimethylformamide, giving 171 mg of the desired product, mp 254°-256° C. (dec.).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:10]=[CH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>>[CH3:22][S:15][C:12]1[CH:11]=[CH:10][C:9]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[CH:14][N:13]=1
Reactant: COS(=O)(=O)OC
Reactant: O=S(c1ccccc1)c1ccc(=S)[nH]c1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(S(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-(phenylsulfinyl)pyridine-2-thione (2.21 g., .01 moles) in 25 ml. of 2.5N sodium hydroxide is treated with 1.6 g. of dimethyl sulfate. After stirring at room temperature for 3 hours, the reaction mixture is extracted with methylene chloride. The extracts are washed with water, dried and evaporated in vacuo to yield 2-(methylthio)-5-(phenylsulfinyl)pyridine.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[N:12]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cc(CO)nc(CO)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCc1cc(OCCN2CCNCC2)cc(CO)n1
Reaction time: 12 h
Yield: 95.6 %

Procedure:
19 ml of a 4M solution of HCl in dioxane are added to 2.3 g of 4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethoxy)-2,6-bis(hydroxymethyl)pyridine in solution in 33 ml of dioxane. After 12 h at AT, the resulting precipitate is recovered by filtration on a sintered glass funnel, taken up in MeOH and then concentrated under RP, and the residue is diluted in 40 ml of an MeOH/water 1/1 mixture. The resulting solution is deposited on Mega BE-SCX, 25GM 150ML (Varian). After washing the phase with MeOH, the product of interest is eluted with a 2N solution of ammonia in methanol. The MeOH/NH3 phase is concentrated under RP. 1.6 g of 4-[2-(piperazin-1-yl)ethoxy]-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: [F:1][C:2]([F:81])([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:80])([F:79])[F:78])=[CH:69][CH:68]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-])=O)=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][CH:48]=2)[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:44])([F:43])[O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:81])([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:79])([F:80])[F:78])=[CH:69][CH:68]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([NH2:53])=[CH:51][CH:52]=2)([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:43])([F:44])[O:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:40])([F:41])[F:42])=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CC(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)Cc2ccc(N)cc2)cc1
Yield: 87.4 %

Procedure:
9.57 g (8.38 mmol) of 2,2-bis(4-nitrobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.93 g of 2,2-bis(4-aminobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:23]>>[ClH:23].[ClH:23].[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]2)=[N:16][CH:17]=1
Reactant: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Product: Cc1ccc(N[C@H]2CC[C@H](N)CC2)nc1

Procedure:
Tert-butyl(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)carbamate (0.9695 g, 3.17 mmol) and hydrogen chloride (4.0 M solution in 1,4-dioxane, 11.02 ml, 31.7 mmol) to stir at room temperature. After 3½ hours the mixture was evaporated to dryness under reduced pressure. The crude trans-N1-(5-methylpyridin-2-yl)cyclohexane-1,4-diamine dihydrochloride was used without further purification.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C:41]4[CH:50]=[CH:49][C:48]5[C:43](=[C:44](O)[CH:45]=[CH:46][CH:47]=5)[N:42]=4)=[N:39][N:40]=3)[CH:37]=2)[CH2:31][CH2:30]1>>[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C:41]4[CH:50]=[CH:49][C:48]5[C:43](=[C:44]([O:9][C@H:8]6[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]6)[CH:45]=[CH:46][CH:47]=5)[N:42]=4)=[N:39][N:40]=3)[CH:37]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(C6CC6)cn45)nc23)CC1

Procedure:
Prepared according to the method of Example 90 using cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place of trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and 2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in Step C and running the reaction at 50° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-tert-butyl 4-oxo-1-piperidinecarboxylate using standard reductive amination conditions. The resulting crude solid was triturated with diethylether to give 4-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid (72% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was stirred in a solution of 2N HCl (5 ml) and methanol (5 ml) overnight, before the solution was evaporated in vacuo to remove the methanol and the acidic solution made basic with sat. aq. K2CO3. The resulting solid was filtered and washed with diethyl ether to give 342 as a solid (52% yield). NMR (CDCl3, 400 MHz), 1.48-1.55 (3H, m), 1.86 (2H, d, J=12.7), 2.38 (3H, s), 2.58-2.64 (3H, m), 3.18 (2H, d, J=12.2), 3.88-3.91 (4H, m), 3.94 (2H, s), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([OH:33])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I.O>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([O:33][CH3:34])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: CI
Solvent: O
Solvent: C1CCOC1
Product: CO[C@]12CC[C@H](c3ccoc3)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]21C
Temperature: 70 °C

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.