Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:17]([N:19]1[CH:23]=[C:22]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:21]=[N:20]1)[CH3:18]>>[CH2:17]([N:19]1[CH:23]=[C:22]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:14]([CH:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])[CH:21]=[N:20]1)[CH3:18]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)CCC2
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(C(C)C)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 68.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.33 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.46 g) was obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:33])[CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][OH:13]>C1COCC1>[CH3:8][N:9]([CH3:33])[CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][O:13][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO)CN(C)C
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(COC(=O)CCC(=O)O)CN(C)C

Procedure:
Succinic anhydride (0.60 g, 5.99 mmol, 1.1 equiv) was added in one portion to a dry THF (11 mL) solution of 3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol (2.0 g, 5.45 mmol, 1.0 equiv) and the resultant was refluxed for 18 hours under argon. The mixture was concentrated and then dissolved in EtOAc (10 mL) and poured into deionized water (20 mL). The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to provide crude 4-(3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)-4-oxobutanoic acid, a thick yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[C:16]=2[CH:15]=[CH:14][N:13]=1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:22]([C:17]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:21]=3[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1OC
Yield: 82 %

Procedure:
3.06 g of 3,4-dimethoxyaniline was dissolved in 30 ml of pyridine, to the solution was added in small portions 5.28 g of 5-isoquinolinesulfonyl chloride·HCl with stirring under ice cooling, and the mixture was stirred for 30 minutes, and further stirred at a room temperature overnight. After evaporating off the pyridine under a reduced pressure and additing 20 ml of water, the mixture was extracted twice with 50 ml of chloroform/isopropanol (10:1). The extract was dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. To the resulting residue was added 20 ml of benzene/chloroform (3:1), and the mixture was slightly warmed and collected to obtain 5.64 g of the title compound as colorless crystals.
Reaction SMILES: [H-].[Na+].C(O[C:12]1[CH:13]=[C:14]([C:19]2[C:20](O)=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]([OH:18])=[CH:16][CH:17]=1)CCCCCCC.I[CH2:27][CH:28]1[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[O:31][C:29]1=[O:30]>CN(C)C=O>[CH2:15]([O:18][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:15]([O:18][CH2:27][C@H:28]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[O:31][C:29]3=[O:30])=[CH:16][CH:17]=[CH:12][CH:13]=2)=[CH:20][CH:21]=1)[CH2:14][CH2:19][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20].[CH2:15]([O:18][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:15]([O:18][CH2:27][C@@H:28]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[O:31][C:29]3=[O:30])=[CH:16][CH:17]=[CH:12][CH:13]=2)=[CH:20][CH:21]=1)[CH2:14][CH2:19][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CC1(C)CCC(CI)C(=O)O1
Reactant: CCCCCCCCOc1ccc(O)c(-c2ccccc2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccccc2OC[C@@H]2CCC(C)(C)OC2=O)cc1
Product: CCCCCCCCOc1ccc(-c2ccccc2OC[C@H]2CCC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thereafter, 0.09 g of 60% sodium hydride was suspended in 5 ml of dimethylformamide, and a solution of 0.63 g of 4'-octyloxybiphenol in 5 ml of dimethylformamide was added to the suspension, and the mixture was stirred at room temperature for 1 hr to conduct a reaction. To the resultant solution was added 0.60 g of 2-iodomethyl-5,5-dimethyl-δ-valerolactone, and stirring was continued at room temperature for two days to conduct a reaction. The reaction mixture was poured into ice water, and the reaction product was extracted with diethyl ether. The extract was washed three times with water and dried over magnesium sulfate, the solvent was removed by distillation under a reduced pressure to obtain a crude product, and the crude product was purified by a silica gel column chromatography to 0.58 g of 2-(4'-octyloxybiphenyloxymethyl)-5,5-dimethyl-δ-valerolactone. The product was subjected to optical resolution by a liquid chromatography, and both components thus obtained were each recrystallized from ethanol to obtain 0.20 g of (2R)-2-(4 '-octyloxybiphenyloxymethyl)-5,5-dimethyl-δ-valerolactone and 0.11 g of (2S)-2-(4'-octyloxybiphenyloxymethyl)-5,5-dimethyl-δ-valerolactone, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:15]O.P(Br)(Br)[Br:18].CCOC(C)=O>C1COCC1>[Br:18][CH2:15][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccccc2)cc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Oc2ccccc2)ccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Dissolve under nitrogen atmosphere (2-fluoro-4-phenoxyphenyl)-methanol (1.41 g, 6.5 mmol) in anhydrous THF (60 mL). Cool to 0° C. in an ice bath. Add phosphorous tribromide (2.11 g, 7.8 mmol). Stir at cold for 1 h, then remove the ice bath and stir at ambient temperature for 16 h. Quench the reaction with saturated aqueous NaHCO3. Extract aqueous phase three times with EtOAc. Combine organic fractions, wash with brine, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1). Evaporate the solvent to obtain the title compound (1.31 g, 72%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)(Cl)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C.C(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC1(c2cc3ccccc3o2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)N2CC(c3cc4ccccc4o3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-benzhydryl-3-(benzofuran-2-yl)-3-chloroazetidine (458 mg, 1.23 mmol) and 10% palladium on carbon (130 mg) in ethyl acetate (6 mL) and ethanol (6 mL) was stirred at room temperature under hydrogen atmosphere (˜1 atm) for 1 day. An additional amount of 10% palladium on carbon (130 mg) was added as well as triethylamine (171 μL, 1.23 mmol) and hydrogenation was continued under same conditions for 3 days. After removal of hydrogen, the mixture was diluted with dichloromethane (50 mL), filtered through Clarcel® and concentrated. The residue was taken up in dichloromethane (30 mL) and washed with aqueous saturated sodium hydrogencarbonate (30 mL). The aqueous layer was back-washed with dichloromethane (2×30 mL) and all the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (100:0 to 95:5) as eluent. The title compound was obtained as a yellow gum (111 mg, 27%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C
Yield: 41.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-(trifluoromethyl)benzoyl chloride (0.256 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.061 g (41% yield) of pure product: MS (ES) m/z 478 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17](/[CH:18]=[CH:19]/[O:20]C)[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]3)[C@H:10]2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.[I-].[K+]>C(#N)C.O.[Hg](OC(C)=O)OC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][CH:19]=[O:20])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]3)[C@H:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:35][CH:36]=1
Reactant: CO/C=C/[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CC=O)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cold solution of 37 (100 mg, 0.18 mmol) in acetonitrile (20 mL) at −5° C. was added a solution of Hg(OAc)2 (68 mg, 0.21 mmol) in water (10 mL) dropwise. After stirred at 0° C. for 4 h, the reaction mixture was treated with potassium iodide (40 mg, 0.24 mmol) in water (1.6 mL) for 10 min. The reaction solution was quenched with water, extracted with dichloromethane (40 mL), and dried over MgSO4. Removal of solvents gave crude 2-((3aR,5R,6R,7R,7aR)-6,7-bis(4-methoxybenzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)acetaldehyde. To a solution of the crude product in dry THF (20 mL) was added NaBH4 (16 mg, 0.42 mmol) at 0° C. in portions. After stirred at 0° C. overnight, the reaction solution was quenched with water (25 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with saturated aqueous NH4Cl, dried over MgSO4, and concentrated to give a residue, which was purified by silica gel chromatography, eluted with 20-50% ethyl acetate in petroleum ether to give the product 38 as a light yellow oil (50 mg, 48%). (ES, m/z)[M+H]+ 503.0; 1H NMR (300 MHz, CDCl3) δ 7.15-7.35 (m, 4H), 6.84-6.98 (m, 4H), 6.28 (d, J=6.3 Hz, 1H), 4.45-4.89 (m, 4H), 4.18 (t, J=5.7 Hz, 1H), 3.94 (t, J=4.8 Hz, 1H), 3.87-3.91 (m, 1H), 3.78 (s, 6H), 3.56-3.65 (m, 3H), 2.92 (s, 6H), 1.89-1.98 (m, 1H), 1.62-1.73 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].[CH3:15][O:16][P:17]([CH3:21])(=[O:20])[O:18][CH3:19]>>[CH3:15][O:16][P:17]([CH2:21][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4])(=[O:20])[O:18][CH3:19]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cnn(C)c1C(F)(F)F
Product: COP(=O)(CC(=O)c1cnn(C)c1C(F)(F)F)OC

Procedure:
This material was obtained in analogy to example step A] from 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid methyl ester (3.3. g) and methyl-phosphonic acid dimethyl ester (3.934 g) to give [2-(1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (4.48 g) as a white solid. MS (ESI): 301.0 (MH+).
Reaction SMILES: [Na].C([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:9]=1[C:21](=O)[CH3:22])C>C(O)C>[CH3:22][C:21]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:5]([OH:4])=[O:24]
Reactant: CCOC(=O)COc1ccc(Cc2cccnc2)cc1C(C)=O
Agent: [Na]
Solvent: CCO
Product: Cc1c(C(=O)O)oc2ccc(Cc3cccnc3)cc12
Yield: 18.7 %

Procedure:
Sodium (0.50 g.) was dissolved in ethanol (10 ml.) and a solution of 2-acetyl-4-(3-pyridylmethyl)phenoxyacetic acid ethyl ester (4.70 g.) in ethanol (15 ml.) was added. The mixture was heated under reflux for 3 hours and then evaporated. The residue was dissolved in water and the solution was washed several times with ether. The aqueous layer was acidified with glacial acetic acid to give a gummy solid which was filtered off, washed with water, dried and chromatographed on silica gel. Elution with chloroform gave some impurity and then further elution with chloroform/methanl (9:1) gave a solid which was crystallized from ethanol to give 3-methyl-5-(3-pyridylmethyl)benzofuran-2-carboxylic acid (0.75 g.) m.p. 223-225° C.
Reaction SMILES: [I:1]I.[Cl:3][S:4]([OH:7])(=[O:6])=[O:5].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>>[S:4]([Cl:3])([O:7][C:10]([F:12])([F:11])[C:9]([I:1])([F:13])[F:8])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: II
Reactant: FC(F)=C(F)F
Product: O=S(=O)(Cl)OC(F)(F)C(F)(F)I
Temperature: 50 °C
Yield: 7.3 %

Procedure:
Into a 400 mL stainless steel shaker tube was charged iodine (101.6 g, 0.4 mol) and chlorosulfonic acid (46.6 g, 0.4 mol). The reactor was cooled and evacuated, then tetrafluoroethylene (50 g, 0.8 mol) was transferred into the reactor. After being agitated and heated at 50° C. for 8 h, the product mixture was poured into ice water and the organic layer was separated. After drying with magnesium sulfate, the mixture was distilled to give low yield of ICF2CF2OSO2Cl (10 g), and a large amount of ICF2CF2Cl.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2([CH3:21])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O.O1CCCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Yield: 89 %

Procedure:
A stirred solution of 8 g. (0.027 mole) of 7-benzoyl-3-methyl-3-methylthioindolin-2-one in 80 ml. of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickel-water mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concentrated hydrochloric acid was added to the filtrate and the dark orange solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid (6.0 g., 89% yield) melted at 125°-127°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:31])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O.CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:31])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 25 °C
Yield: 165 %

Procedure:
A suspension of methyl 3′-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino][1,1′-biphenyl]-3-carboxylate hydrochloride (10 g) and methanol (67 ml) at 40-50° C. is treated with 1.5N aqueous sodium hydroxide (60 ml) and held at this temperature for at least 1 hour. This solution is added to a solution of concentrated hydrochloric acid (10 ml) in water (20 ml) and methanol (33 ml) at 50° C. The resulting suspension is cooled to room temperature and filtered to give the title compound (8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])[CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)[C:19]3=[O:27])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrCc1cccnc1
Product: O=C1N(Cc2cccnc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 78 starting from 3-bromomethyl-pyridine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C29H27ClN2O2: 470, observed (M+H)+: 471.2 1HNMR (400 MHz, MeOD-d4) δppm 2.25 (dd, J=8.59, 1.77 Hz, 2 H) 3.31 (br. s., 1 H) 5.28 (d, J=3.03 Hz, 2 H) 6.12 (d, J=7.58 Hz, 1 H) 6.71-6.85 (m, 1 H) 7.03 (d, J=8.08 Hz, 1 H) 7.12-7.19 (m, 1 H) 7.21-7.29 (m, 2 H) 7.30-7.39 (m, 2 H) 7.86-7.99 (m, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.74 (d, J=5.31 Hz, 1 H) 8.84 (s, 1 H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+].I([O-])(=O)(=O)=O.CO>C(Cl)(Cl)Cl.CO>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Reaction time: 0.25 h

Procedure:
Digoxin (0.4985 g, 0.64 mmole) was dissolved in 10 ml of chloroform/methanol (3/1.5) and placed into a 100 ml two-necked flask. Sodium periodate (0.3102 g, 1.4 mmoles) was dissolved in 4 ml distilled water and placed into a pressure equalized addition funnel. The periodate solution was slowly added to the flask while stirring and under nitrogen. A white precipitate was immediately formed and the reaction was complete within 15 minutes after addition of the periodate. Reaction progress was monitored by TLC (E. M. Merck, pre-coated TLC sheets, silica gel 60 F254 0.2 mm thickness) in chloroform/methanol 10/1 by volume Rf 0.16=dialdehyde, one homogeneous spot; Rf 0.07=Digoxin. Both spots became dark brownish when the TLC plate was sprayed with methanol/concentrated sulfuric acid (9/1 by volume) and placed in an oven at 100° C. The reaction mixture was evaporated on a rotatory evaporator and brought up in 30 ml of chloroform and 3 ml of water. The cloudy solution was extracted and the aqueous layer washed three times with 10 ml chloroform. The organic phases are combined (60 ml) and dried over magnesium sulfate. The organic solvents are evaporated to dryness. A light yellow brownish oily material was left. This material was used immediately in the next reaction.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:25]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38]([OH:40])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.[N+:50]([C:53]1[CH:58]=[C:57]([NH2:59])[CH:56]=[CH:55][C:54]=1[NH2:60])([O-:52])=[O:51]>CN(C=O)C>[NH2:60][C:54]1[CH:55]=[CH:56][C:57]([NH:59][C:38]([C@H:33]2[CH2:34][CH2:35][CH2:36][CH2:37][N:32]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:40])=[CH:58][C:53]=1[N+:50]([O-:52])=[O:51]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)—N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then 2-nitro-1,4-phenylenediamine (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g).