Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:47])[N:20]([CH2:37][O:38][C:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[O:40])[C:21](=[O:36])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=3)[N:25]([CH3:35])[CH:24]=2)=[CH:10]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:3]([OH:5])(=[O:4])[CH3:2].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:47])[N:20]([CH2:37][O:38][C:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[O:40])[C:21](=[O:36])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=3)[N:25]([CH3:35])[CH:24]=2)=[CH:10]1
Reactant: O=C(O)C(F)(F)F
Agent: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(COC(=O)C3CCNCC3)C2=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)O

Procedure:
Piperidine-4-carboxylic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester trifluoroacetate, prepared as in example 8a above, was dissolved in ethyl acetate. The resulting solution was neutralized with cold saturated NaHCO3. The ethyl acetate layer was concentrated and slurried in H2O and acidified with excess HOAc and lyophilized to give the desired product (yield—97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1>O.C(O)(=O)C.C(O)CC.C(OC(=O)C)C.[Fe]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnccc1-c1ccc(Cl)cc1
Agent: [Fe]
Solvent: O
Solvent: CCCO
Solvent: CCOC(C)=O
Product: Nc1cnccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In a sulfonation flask 8.4 g (36 mmol) 4-(4′-chlorophenyl)-3-nitropyridine is dissolved in a mixture of 100 ml water, 35 ml acetic acid and 10 ml n-propanol. After the addition of 7.0 g (125 mmol) iron powder, the mixture is heated for 3 hours under reflux conditions. After cooling to room temperature the mixture is diluted with ethylacetate and filtered over hyflo. Then the filtrate is neutralized by the addition of sodiumbicarbonate solution and the organic phase separated. The water phase is extracted twice with ethylacetate and the combined organic phases dried over sodium sulfate. After distilling off the solvent in a water jet vacuum the obtained raw material is purified by column chromatography over silica gel (eluant: ethylacetate). Yield: 3.9 g 3-amino-4-(4′-chlorophenyl)pyridine in the form of a slightly brownish powder; m.p.: 144–146° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH2:19][CH2:20][CH:21]([NH:24][C:25](=O)[CH2:26][CH3:27])[C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH2:19][CH2:20][CH:21]([NH:24][CH2:25][CH2:26][CH3:27])[C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NC1CCCc2ncc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: CCCNC1CCCc2ncc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc21
Yield: 57.9 %

Procedure:
Following the same procedure as described above, N-[3-(4-isopropylbenzenesulfonylamino)-5,6,7,8-tetrahydro-quinolin-5-yl]-propionamide (136 mg, 0.33 mmol) in THF (10 ml) was treated with 1M BH3.THF (3.3 ml). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 1:2) provides the title compound (74 mg, 56%) as a white solid.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=C.BrBr.[CH:13]1C=CC=C[CH:14]=1>>[CH:9]([C:4]1[CH:3]=[CH:8][C:7]([CH:13]=[CH2:14])=[CH:6][CH:5]=1)=[CH2:10]
Reactant: c1ccccc1
Reactant: C=Cc1ccccc1C=C
Agent: BrBr
Product: C=Cc1ccc(C=C)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
Pure 1,4-divinylbenzene (1,4-DVB) monomer was isolated from commercially available divinylbenzene mixture (Aldrich Chemical Co.), containing about 60 wt. % divinylbenzene and having a mole ratio between the 1,3- and 1,4-isomer of about 1 to 2.5, by a bromination-debromination method. In a 1 L flask equipped with a magnetic stirring bar, 230 ml of the commercial divinylbenzene mixture was mixed with 500 ml of benzene. Under stirring and cooling at 0° C., 120 ml of bromine was dropwised into the mixed solution for a period of 6 hours. During the bromine addition, the color of solution changed from deep red through brown yellow to light yellow. At the last stage, the tetrabromided 1,4-divinylbenzene was crystallized and the solution became gray white. The crystals were filtered and washed with methanol until complete decoloration. The resulting crystals were recrystallized twice from chloroform, filtered and dried. About 95 g of the tetrabromided 1,4-divinylbenzene, i.e. 1,4-bis(1,2-dibromoethyl)benzene, was obtained. The crystals were analyzed by DSC and NMR. DSC showed a melting point at 163° C. 1H NMR spectra showed the expected chemical shifts: 67 =7.45 (singlet, 4H, C6H4), 5.15 (multiplet, 2H, CHBrCH2Br), and 4.10 (multiplet, 4H, CHBrCH2Br).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])[CH3:21].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2) (0.6 g, 0.86 mmol), triphenylphosphine (0.44 g, 1.74 mmol), (2-acetylphenyl)boronic acid (6 g, 3.76 mmol) and tripotassium phosphate hydrate (16 g, 7.54 mmol) were placed in a flask. Nitrogen was blown into the flask and then the flask was filled with toluene (40 ml) and 4-chlorbenzonitrile (4 g, 2.90 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled and washed with water. The organic layer was dried over sodium sulfate and then the solvent was evaporated. The product, 2′-acetyl-4-biphenylcarbonitrile (5a) was purified by a column (hexane/ethyl acetate=8/1). Yield: 3.3 g (51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[N:42]=[C:43]=[O:44]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[NH:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1)=[O:44]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 3-(4-amino-2-methylphenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (92 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol) in 2.5 mL CH2Cl2 at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.065 mL, 0.45 mmol) and the reaction stirred at rt. After 2.5 hours the reaction was quenched with 0.3 mL MeOH, and then stored overnight in the refrigerator. The reaction mixture was filtered and rinsed with EtOAc to give the title compound as an off-white solid (130 mg, 84%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 9.09 (s, 1H), 8.87 (d, J=2.9 Hz, 1H), 8.63 (dd, J=7.5, 2.2 Hz, 1H), 7.99 (dd, J=7.9, 1.2 Hz, 1H), 7.33-7.53 (m, 4H), 7.24-7.29 (m, 1H), 7.13-7.17 (m, 1H), 7.00-7.10 (m, 2H), 4.15-4.23 (m, 1H), 3.64-3.73 (m, 1H), 3.46-3.56 (m, 2H), 3.07-3.15 (m, 1H), 2.33 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[O:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:34][CH:32]2[CH2:33][O:30][CH2:31]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: NC1COC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with oxetan-3-amine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=469.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1)=O>>[C:40]([CH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1)([OH:42])=[O:41]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Yield: 93.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (360 mg) according to an analogous synthetic method to Example 212, the title compound (375 mg) was obtained.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][C:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O>CO.[OH-].[OH-].[Pd+2]>[C:25]([O:24][C:22]([NH:21][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Yield: 98.7 %

Procedure:
A solution of 1.56 g (4.0 mmoles) of N-carbobenzyloxy-4-(tert-butyloxycarbonylamino)-4-carbomethoxy-piperidine in 150 ml of methanol was hydrogenated at 50 psi (20° C.) on a Parr apparatus for 18 hours, using 1.01 g of Pearlman's catalyst (palladium hydroxide on carbon; palladium hydroxide content 20%, water content 31%). The catalyst was filtered and the filtrate concentrated in vacuo to afford the title compound (1.02 g; 100% yield) as a colorless amorphous solid. 1Hnmr (60 mHz, CDCl3) delta 1.23 (9H, s), 1.8-2.35 (4H, broad m), 2.78-3.23 (4H, broad m), 3.77 (3H, s).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH:28]C(OC(C)(C)C)=O)=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:53]>CO>[ClH:53].[ClH:53].[ClH:53].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][NH2:45])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH2:28])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1csc(N)n1
Yield: 92.1 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.), conc. hydrochloric acid (2.9 g.) and methanol (50 ml.) were treated in a similar manner to that of Example 8-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid trihydrochloride (syn isomer, 2.9 g.).
Reaction SMILES: Cl.[CH:2]1([N:8]([CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(OCC)(=O)C.CO.[Pd]>[ClH:25].[CH:2]1([N:8]([CH2:10]/[CH:11]=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(CC#Cc1ccc(C2CCCCC2)c(Cl)c1)C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C/C=C\c1ccc(C2CCCCC2)c(Cl)c1)C1CCCCC1
Yield: 85 %

Procedure:
A solution containing 13.1 g of the compound prepared in Example 1, in the form of the base, and 1.2 g of 5% palladium on barium sulfate in 100 ml of ethyl acetate and 5 ml of methanol is hydrogenated at normal temperature and pressure. The volume of hydrogen absorbed is 650 ml. After filtration and concentration of the solution, the residue is taken up in ethyl ether and the hydrochloride is precipitated by bubbling hydrogen chloride. 5.6 g of the expected compound are obtained after recrystallization from acetonitrile. Yield: 43%.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[C:14]2[O:15][CH2:16][C:17](=[O:19])[NH:18][C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:9]1[C:14]2[O:15][CH2:16][C:17](=[O:19])[N:18]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN1C(=O)COc2c(Cl)nc(C)nc21
Yield: 68.7 %

Procedure:
A solution of 0.41 g of ethyl chloroacetate in 5 ml of methyl ethyl ketone is dropped to a mixture containing 0.6 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.5 g of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone within 15 minutes under refluxing and stirring. Then the mixture is refluxed under stirring for 8 hours, filtered as hot and washed with methyl ethyl ketone. The filtrate is evaporated to 10 ml, cooled and the unchanged starting material is filtered out. The mother liquor is evaporated, the residue is triturated with n-hexane, the solid precipitate is filtered, washed with n-hexane and dried to give 0.59 g (68%) of product, m.p.: 69°-70° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]2=3)[CH2:21][CH2:20][O:19]4)[C:5]1=[O:24].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:1][C@@H:2]([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]2=3)[CH2:21][CH2:20][O:19]4)[C:5]1=[O:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a stirred solution of 1′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.19 mg, 0.56 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.71 mmol). The solution was stirred at ambient temperature for 30 min, then benzylbromide (0.14 g, 0.84 mmol) was added. The reaction mixture was stirred for 16 h. The solution was cooled to ambient temperature, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (25%) to afford 1′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.20 g, 77%) as a colorless solid: mp 45-47° C.; 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.30-6.97 (m, 9H), 6.38 (s, 1H), 6.33 (d, J=36.0 Hz, 1H), 4.84 (dd, J=21.7, 8.9 Hz, 1H), 4.68-4.55 (m, 2H), 4.49 (dt, J=8.6, 0.8 Hz, 2H), 4.40 (dd, J=12.0, 3.8 Hz, 1H), 4.01-3.83 (m, 2H), 3.80-3.68 (m, 1H), 2.88 (t, J=8.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.1 (2), 161.7 (2), 161.3 (2), 143.0 (2), 138.3 (2), 132.7, 128.6, 128.3 (2), 127.5 (2), 127.3, 123.6 (2), 123.2, 120.3 (2), 119.8 (2), 118.9 (2), 109.7 (2), 93.2, 80.7 (2), 73.2, 72.8, 72.4, 70.9, 70.7, 57.6, 46.1 (2), 29.0 (2), 17.7 (2); MS (ES+) m/z 428.0 (M+23).
Reaction SMILES: C([O:4][CH2:5][C@:6]12[O:13][C@:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)[CH:15]=3)([O:11][CH2:12]1)[C@H:9]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:8]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:7]2[OH:47])(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[CH2:40]([O:39][C@@H:8]1[C@@H:9]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@:10]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=4)[CH:15]=3)[O:13][C@@:6]([CH2:5][OH:4])([CH2:12][O:11]2)[C@@H:7]1[OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
To a solution of [(1R,2R,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]methyl acetate 28i (237 mg, 0.36 mmol) in methanol (20 mL) was added potassium carbonate (199 mg, 1.44 mmol) at room temperature. The mixture was stirred at room temperature for 5 min and adjusted with saturated aqueous ammonium chloride till pH becomes 7. The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28j as a white solid (222 mg, 100%).
Reaction SMILES: [C:1](=[O:40])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1>C(Cl)Cl>[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][NH:49][C:1](=[O:40])[O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)[CH2:43][CH2:42]1
Reactant: NCCN1CCOCC1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCOCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 61.4 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added 2-morpholinoethanamine (70.2 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbamate (18 mg, 61.4%) as a white solid. LRMS (M+H+) m/z 543.4. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.82 (m, 1H), 3.59 (m, 4H), 3.16 (m, 2H), 2.46 (m, 2H), 2.41 (m, 5H), 1.08-2.15 (m, 21H), 0.87 (s, 3H), 0.61 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20].C(Cl)(=O)C(Cl)=O.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C)C=O.C1COCC1.C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20]
Reactant: OCc1ccccc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)O)cc3CC[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)OCc4ccccc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 8 %

Procedure:
A 50 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-carboxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.37) and 2 mL of benzene. Oxalyl chloride (1.1 mmol) was added dropwise via syringe to the stirred mixture, followed by a catalytic amount of dimethylformamide (one drop). The mixture was allowed to stir at room temperature for 25 min, and then the volatiles were removed in vacuo. One mL of THF was added, followed by a solution of benzyl alcohol and pyridine (4 eq) in 1 mL of THF at 0°. It was then allowed to warm to room temperature, diluted with 50 mL of chloroform, and washed with 0.1N hydrochloric acid (2×25 mL), 10% sodium bicarbonate (2×25 mL), water, (2×25 mL), and brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on silica (ethyl acetate eluent), to give 11 mg (8%) of the title compound as an amorphous yellow foam. FDMS: m/e=349.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH3:16])[C@H:13](O)[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][NH:48][S:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:45]=[CH2:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:44]([O:47][N:48]([C@H:13]1[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH:15]=[C:14]1[CH3:16])[S:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:45]=[CH2:46]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 77.5 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 8, 19.45 g, 54.40 mmol) in toluene (300 mL) at room temperature was added triphenylphosphine (17.06 g, 65.28 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 14.05 g, 54.40 mmol) and diisopropyl azodicarboxylate (12.85 mL, 65.28 mmol). After 2 hours the reaction mixture was concentrated onto silica gel and purified. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the desired product (25.2 g, 78%) as a yellow oil.