Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].O>N1C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[S:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:20])=[O:18]
Reactant: Oc1cccc2ncccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccc2ncccc12)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 5-hydroxy-quinoline (8 g, 55 mmol) and K2CO3 (15.2 g, 110 mmol) in anhydrous pyridine (60 mL) under nitrogen was cooled to −20° C. Tf2O (13.97 mL, 83 mmol) was added drop-wise via syringe. The reaction mixture was stirred 1 hour at −20° C. then warmed to 0° C. for 1 hour then stirred at ambient temperature for 48 hours. The reaction mixture was then poured into H2O (200 mL) and extracted in CH2Cl2 (2×200 mL). The aqueous layer was acidified with 1 N HCl (100 mL) and back extracted with CH2Cl2 (2×200 mL). The organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (40% EtOAc/Hexanes) affording 13.97 g (90%) of the product as a pink oil: MS EI m/e 277 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[F:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[F:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: NC1=NC(c2ccc(F)c(Br)c2)(c2ccncc2F)c2ccccc21
Product: COc1cccc(-c2cc(C3(c4ccncc4F)N=C(N)c4ccccc43)ccc2F)c1F
Yield: 25 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Example 70) as described in Example 67 Scheme #10, D in 25% yield using 2-fluoro-3-methoxyphenyl boronic acid. 1H NMR (DMSO-d6) δ 8.39 (d, J=3.03 Hz, 1 H), 8.26 (d, J=5.05 Hz, 1 H), 7.83-7.73 (m, 1 H), 7.71-7.64 (m, 1H), 7.48-7.39 (m, 2 H), 7.29-7.11 (m, 6 H), 6.92 (br s, 2 H), 6.81-6.73 (m, 1 H), 3.79 (s, 3 H); MS (ESI) m/z 446 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(N(C(C)C)C(C)C)C.C(NC(C)C)(C)C>CN(C=O)C.[Cu]I>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: C#Cc1ccc(OCCN(CC)CC)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(Br)cn2)cc1
Temperature: 100 °C

Procedure:
A mixture of 500 mg (2.30 mmol) diethyl-[2-(4-ethynyl-phenoxy)-ethyl]-amine, 545 mg (2.30 mmol) 2,5-dibromopyridine, 161 mg (0.23 mmol) tetrakis-triphenylphosphane-palladium, 13 mg (0.07 mmol) CuI, 2 mL ethyldiisopropylamine and 2 mL diisopropylamine in 50 mL DMF is heated for 20 h at 100° C. under a nitrogen atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:17])[N:11]=2)[CH:7]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH2:25])[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])(=[O:17])=[O:18])[N:11]=2)[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C(Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1
Yield: 100 %

Procedure:
2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl]-propionic acid methyl ester, (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) in methanol (40 mL) were agitated for 3.0 h under 55 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (1.01 g, quantitative yield) as a sticky gum. 1H-NMR (CDCl3, 300 MHz) δ 8.45 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 3.79–3.73 (m, 1H), 3.73 (s, 3H), 3.56–3.50 (m, 2H), 5.12 (dd, J=13.5, 5.12 Hz, 1H), 4.85 (dd, J=13.5, 8.1 Hz, 1H), 2.58 (s, 3H), 0.87–0.81 (m, 2H), 0.01 (s, 9H). 13C-NMR (CDCl3, 75 MHz) δ 175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, −2.1. Mass spec.: 398 (MH)+.
Reaction SMILES: B(Cl)(Cl)Cl.C([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23]([NH:25][C:26]3[NH:30][N:29]=[C:28]([CH:31]4[CH2:33][CH2:32]4)[CH:27]=3)[C:22]([C:34]#[CH:35])=[CH:21][N:20]=2)[CH:14]=1)(=[O:12])=[O:11])(C)(C)C>C(Cl)Cl>[CH:31]1([C:28]2[NH:29][N:30]=[C:26]([NH:25][C:23]3[C:22]([C:34]#[CH:35])=[CH:21][N:20]=[C:19]([C:15]4[CH:14]=[C:13]([S:10]([NH2:9])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=4)[N:24]=3)[CH:27]=2)[CH2:33][CH2:32]1
Reactant: C#Cc1cnc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)nc1Nc1cc(C2CC2)n[nH]1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
BCl3 (1 M in CH2Cl2, 0.92 mL, 0.92 mmol, 5 equiv.) was added to a stirred solution of N-tert-butyl-3-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl)benzenesulfonamide (80 mg, 0.18 mmol, 1.0 equiv.) in CH2Cl2 (20 mL) at room temperature under nitrogen. The reaction mixture was stirred for 30 min and quenched with aq. NaHCO3 under an ice bath. The reaction mixture was extracted with ethylacetate and washed with water, brine, dried, filtered and evaporated. The crude product was crystallized with THF/isopropyl to afford the title compound 3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)benzene sulfonamide (Compound 110) (40 mg, 57%). LC-MS (m/z)=380.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.82 (m, 2H), 0.96-0.98 (m, 2H), 1.94 (m, 1H), 4.90 (s, 1H), 6.47 (s, 1H), 7.45 (s, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.62 (s, 1H), 8.70 (s, 1H), 8.82 (s, 1H), 12.31 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>N1C=CC=CC=1.CCOC(C)=O>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:4]1[CH:3]=[C:2]([NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH:7]=[CH:6][CH:5]=1)#[N:20]
Reactant: CCN=C=O
Reactant: CCn1c(C#Cc2cccc(N)c2)c(C#N)c2ccc(OC)cc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cccc(C#Cc2c(C#N)c3ccc(OC)cc3n2CC)c1
Temperature: 100 °C
Yield: 35.6 %

Procedure:
2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) is added. The reaction mixture is then heated at 100° C. for 2 h. The mixture is then diluted in EtOAc, and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CH2Cl2/EtOAc), followed by trituration with hexanes/acetone (1/1), yields 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N-:23]=[N+]=[N-].[Na+].O.[OH-].[Na+]>Cl>[O:1]=[C:2]1[NH:23][CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CCN1
Temperature: 50 °C

Procedure:
To a solution of (3S)—N-(4-oxocyclohexyl)-1-phenylpiperidine-3-carboxamide (10 mg, 0.00003 mol, prepared as example 171) in concentrated aqueous HCl (0.5 mL), was added sodium azide (2.27 mg, 0.0000350 mol) in small portions over 3 minutes with slow agitation. The temperature was slowly increased to 50° C. The reaction temperature was maintained at 50° C. for 8.5 h and then poured into 50 g of crushed ice and water. The solution was basified with cold 50% NaOH and the resulting solution was extracted with EtOAc(×3). The EtOAc extracts were combined, dried over MgSO4, filtered and evaporated to yield the crude product, which was purified by prep-HPLC. LCMS: (M+H)+=316.2.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].ON1C2C=CC=CC=2N=N1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.O>[N:21]1([CH2:20][CH2:19][NH:18][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C#CCCC(=O)O
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCC(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-pentynoic acid (981 mg, 10 mmol) was added anhydrous 1-hydroxybenzotriazole (8.11 g, 60 mmol), followed by addition of N,N-dimethylformamide (55 mL) and the mixture was stirred at room temperature until a yellow solution resulted. A solution of 4-(2-aminoethyl)-morpholine (1.31 g, 10.1 mmol) in N,N-dimethylformamide (10 mL) was added, followed by addition of triethylamine (8.35 mL, 60 mmol). After stirring for about 10 min, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.73 g, 35 mmol) was added and stirring at room temperature was continued overnight. The reaction mixture was diluted with water and was extracted successively with diethyl ether, ethyl acetate, dichloromethane and chloroform/i-propanol (9:1). The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum. The solid residue was purified by silica gel flash chromatography using dichloromethane/methanol (9:1) as eluent to provide Example 646. MS (DCI-NH3): m/z 211 (M+H)+.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>C(O)CC>[N:8]1[C:3]2[N:4]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:2]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccc[n+]1COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCO
Product: C1=CN2COc3ccccc3N=C2N=C1
Yield: 60.2 %

Procedure:
A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)-methyl]pyrimidinium chloride, 8.3 g of potassium carbonate, and 0.4 g of copper-bronze in 150 ml of n-propanol, under N2, is heated under reflux for about 7 days while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dryness. The residue is dissolved in 400 ml of ether, the ether solution is washed, dried and the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 g of the title product.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([S-:11])#[N:10].[K+].BrBr.O>C(O)(=O)C>[F:1][C:2]1[N:7]=[C:6]2[S:11][C:9]([NH2:10])=[N:8][C:5]2=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)nc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(F)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
6-Fluoropyridin-3-amine (4 g, 35.7 mmol) was added to a mechanically stirred suspension of potassium rhodanate (27.7 g, 285 mmol) in acetic acid (89 mL) at 0° C. The flask 3-neck flask was then fitted with an addition funnel charged with bromine (5.70 mL, 111 mmol) in acetic acid (29.7 mL). The bromine solution was added over 30 min and the solution turned into a viscous and yellow mixture. After bromine addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred at that temperature for 16 h. Water (30 mL) was added to the reaction mixture and it was heated to 85° C. for 20 min before the solids were filtered and washed with water and methanol to give 5-fluorothiazolo[5,4-b]pyridin-2-amine (4.18 g, 24.71 mmol, 69.2% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11][CH3:12])=[O:10].Cl.[NH2:15][OH:16].O.Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:15][OH:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(=NO)c1ccccc1O

Procedure:
3.3 g (0.016 mol) of methyl 2-hydroxyphenylglyoxylate (HPLC: 88%, log p=1.87) (Example VI-1a) and 1.3 g (0.019 mol) of hydroxylamine hydrochloride in 50 ml of methanol are heated under reflux for one hour. The reaction mixture is poured into water, acidified with 2N hydrochloric acid and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 2.4 g of crude product which, according to HPLC, contains 17.1% of methyl E-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=0.95 and 68.9% of methyl Z-2-(2-hydroxyphenyl)-2-hydroxyimino-acetate of log p=1.68.
Reaction SMILES: C[C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:9]=1[CH3:25])=[O:7].[F:30]C1C=CC=CC=1C=O.C(O)C.[OH-].[K+]>C(OCC)(=O)C>[F:30][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:9]=1[CH3:25])=[O:7]
Reactant: O=Cc1ccccc1F
Reactant: Cc1ccccc1C=CC(=O)c1c(C)n(CCN2CCOCC2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C=Cc2ccccc2F)c2ccccc2n1CCN1CCOCC1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 20A above, 14.75 g. (0.0516 mole) of 3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml. of ethanol in the presence of 3.44 g. (0.061 mole) of potassium hydroxide pellets and the product, in the form of the free base, recrystallized from ethyl acetate to give 10.0 g (54%) of 3-(2-fluorocinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 113°-116° C.
Reaction SMILES: [CH2:1]([Si:3]([CH2:35][CH3:36])([CH2:33][CH3:34])[O:4][C@H:5](/[CH:18]=[CH:19]/[Sn](CCCC)(CCCC)CCCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:2].C([Li])CCC.[Cu](C#N)C#N.C[Li].[CH2:49]([Si:51]([CH2:73][CH3:74])([CH2:71][CH3:72])[O:52][C@@H:53]1[CH2:57][C:56](=[O:58])[C:55]([CH2:59]/[CH:60]=[CH:61]\[CH2:62][CH2:63][CH2:64][C:65]([O:67][CH:68]([CH3:70])[CH3:69])=[O:66])=[CH:54]1)[CH3:50].[NH4+].[Cl-].[NH4+].[OH-]>O1CCCC1>[F:15][C:14]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][C@H:5]([O:4][Si:3]([CH2:33][CH3:34])([CH2:35][CH3:36])[CH2:1][CH3:2])/[CH:18]=[CH:19]/[C@H:54]1[C@H:53]([O:52][Si:51]([CH2:49][CH3:50])([CH2:71][CH3:72])[CH2:73][CH3:74])[CH2:57][C:56](=[O:58])[C@@H:55]1[CH2:59]/[CH:60]=[CH:61]\[CH2:62][CH2:63][CH2:64][C:65]([O:67][CH:68]([CH3:70])[CH3:69])=[O:66]
Reactant: CCCC[Sn](/C=C/[C@H](COc1cccc(C(F)(F)F)c1)O[Si](CC)(CC)CC)(CCCC)CCCC
Reactant: CC[Si](CC)(CC)O[C@H]1C=C(C/C=C\CCCC(=O)OC(C)C)C(=O)C1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@H](/C=C/[C@H]1[C@H](O[Si](CC)(CC)CC)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC(C)C)COc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A 500 mL three-necked flask was flame dried and allowed to be cooled under nitrogen. (R,E)-triethyl ((4-(tributylstannyl)-1-(3-(trifluoromethyl)phenoxy)but-3-en-2-yl)oxy)silane (22.53 g, 35.46 mmol) and 200 mL tetrahydrofuran were added to the reaction flask, followed by dropwise addition of n-butyl lithium (22.2 mL, 1.6 M in hexane) at −70° C. A suspension solution of copper cyanide (3.18 g, 35.46 mmol) in 30 mL tetrahydrofuran was cooled to −10° C. and followed by dropwise addition of methyl lithium (17.76 mL, 2 M in ether). The homogenous organo-metallic solution was cooled and added into the reaction flask while stirring for 30 minutes. Then, a solution of (R,Z)-isopropyl 7-(3-triethylsilyloxy-5-oxocyclopent-1-en-1-yl)hept-5-enoate (4.5 g, containing 5% of 5,6-trans isomer) in 15 mL tetrahydrofuran at −70° C. was added to the reaction mixture for 10 minutes. After being stirred for another 20 minutes, the reaction mixture was poured into a mixture of 9/1 (v/v) saturated aqueous NH4Cl/NH4OH solution to be phase separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous MgSO4. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the title compound was 5.10 g (59.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[C:23]([O:29][CH3:30])=[CH:22][C:3]=1[CH2:4][CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>CO.[Zn]>[NH2:26][C:24]1[C:23]([O:29][CH3:30])=[CH:22][C:3]([CH2:4][CH2:5][N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:25]=1
Reactant: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1N
Temperature: 45 °C
Yield: 73.8 %

Procedure:
To a solution of tert-butyl 2-chloro-5-methoxy-4-nitrophenethyl(3-fluorobenzyl)-carbamate (0.7 g, 1.59 mmol) in methanol (30 mL), saturated solution of NH4Cl (30 mL) was added followed by zinc powder (0.52 g, 7.98 mmol) and the mixture heated to 45° C. for 1.0 h. The mixture was allowed to cool to room temperature, filtered through celite then partitioned between EtOAc (25 mL) and water (50 mL). The separated aqueous phase was extracted with EtOAc (50 mL), then the combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.48 g, 74%).
Reaction SMILES: S1C=CC=C1[CH2:6][C:7](O)=[O:8].[N:10]([C@@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH3:25])[CH2:14]1)=[N+]=[N-]>>[C:7]([NH:10][C@@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH3:25])[CH2:14]1)(=[O:8])[CH3:6]
Reactant: O=C(O)Cc1cccs1
Reactant: C[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Product: CC(=O)N[C@H]1C[C@H](C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Under a nitrogen atmosphere, 0.27 mL (280 mg, 3.7 mmol) of thiolacetic acid was added to 210 mg (0.93 mmol) of (2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine. The reaction mixture was stirred at room temperature for approximately four hours and concentrated with a rotary evaporator. The resulting oil was subjected to flash column chromatography using 1:1 ethyl acetate/hexane followed by ethyl acetate as eluant to obtain 190 mg of (2S,4S)-4-acetamido-1-t-butoxycarbonyl-2-methylpyrrolidine (84% yield) as a yellow oil which solidified on standing. Recrystallization of a small sample from hexanes provided a white solid, mp 108-110 degrees C. The material thus obtained was found to be identical to the material obtained by a two-step procedure that provides for the hydrogenation of (2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine with hydrogen and Pd/C followed by a separate acetylation step utilizing acetic anhydride.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[C:52]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:58]=[CH:59][CH:60]=3)[CH:46]([O:69][CH3:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4cccc5ccc(O)cc45)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH2Cl2 (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10% solution). The flask was capped and the mixture stirred 4 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) to afford 44.2 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-4-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Rf =0.23). (1H NMR and mass spectral analysis were consistent with the desired structure).