Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:7][CH2:6]1)C=C.[BH4-].[Na+]>C(Cl)CCl.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[C:41]([O:40][C@@H:34]([C:12]1[C:13]([CH3:33])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:45])([O:4][CH2:1][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH3:44])([CH3:42])[CH3:43]
Reactant: C=CCCc1ccccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (55 mg, 0.089 mmol) and (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (5.57 mg, 8.89 μmol) in ClCH2CH2Cl (60 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (5 mL). Sodium borohydride (3.36 mg, 0.089 mmol) was added and the reaction was stirred at rt for 1 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purify by biotage, eluting with 20% EtOAc/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (37 mg, 70%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38-7.15 (m, 4H), 6.57 (s, 1H), 6.07 (s, 1H), 4.82-4.69 (m, 4H), 4.59 (t, J=11.2 Hz, 1H), 4.28-4.12 (m, 2H), 3.91 (t, J=10.9 Hz, 1H), 3.44 (d, J=7.3 Hz, 2H), 3.05 (d, J=11.3 Hz, 1H), 2.89 (dd, J=14.2, 6.4 Hz, 1H), 2.78 (dd, J=13.8, 8.3 Hz, 2H), 2.63 (s, 3H), 2.03-1.89 (m, 2H), 1.88-1.64 (m, 8H), 1.28 (s, 3H), 1.25 (s, 9H), 1.24-1.19 (m, 3H). LCMS (M+1)=593.4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:17]([OH:20])(=O)[CH3:18].C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[OH:33][C@@H:34]1O[C@H](CO)[C@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]1[OH:36].C1([O-])C=CC=CC=1.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1Br)(=O)C.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC1C=C2C(C(CC([O-])=O)=CC(=O)O2)=CC=1)(=O)C>>[C@@H:34]1([O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]3)=[CH:4][CH:3]=2)[O:33][C@H:18]([CH2:17][OH:20])[C@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]1[OH:36]
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CC(=O)O
Reactant: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2ccc3c(CC(=O)[O-])cc(=O)oc3c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [O-]c1ccccc1
Product: O=C(O)Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12

Procedure:
In accordance with exemplary Scheme 1, the carboxy function of 7-Hydroxycoumarin-4-acetic acid 1 (available from Aldrich Chemical Co., Milwaukee, Wis.) is protected by, for example, conversion to the methyl ester 2 via the Fischer Spier reaction using a procedure described by Baker, W., Haksar, C. N., McOmie, J. F. W., J. Chem. Soc. 170-173 (1950). An enzyme cleavable group can then be added to the remaining hydroxyl function at the 7 position. For example, β-D-galactopyranoside tetraacetate 3 is prepared by reaction of the phenolate anion of compound 2 with tetra-O-acetyl-α-D-galactopyranosyl bromide (available from Sigma Chemical Co., St. Louis, Mo.) using a procedure described by Baggett et al. in Carbohydrate Research 197, 295-301, (1990). The protected species then can be deprotected. As shown in Scheme 1, 7-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)coumarin-4-acetate 3 is hydrolysed to give 7-β-D-galactopyranosyloxycoumarin-4-acetic acid 4 using the procedure described by Baggett et al. in Carbohydrate Research 197, 295-301, (1990). Compound 4 can then be modified with a suitable amine functional group to yield the final product. Scheme 1 demonstrates conversion of compound 4 to the pentafluorophenyl ester and then reaction with ethanolamine to give the compound 5. Compound 5 can also be obtained from compound 3 as outlined in Scheme 1.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:13][C:14]([CH3:28])([CH2:19][C:20](=O)[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]([O:17]C)=[O:16]>>[Cl:1][C:8]1[CH:9]=[CH:10][C:5]([CH2:2][N:11]2[C:8]3[C:7](=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=3)[C:21]([S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:20]2[CH2:19][C:14]([CH3:28])([CH3:13])[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: Cl
Reactant: CC(C)c1ccc(NN)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1[-(4-(i-propyl)phenyl]hydrazine hydrochloride and methyl 2,2-dimethyl-5-(t-butylthio)-4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 189°-192°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].O[Li].O.Cl>C1COCC1.CO.O.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cl
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
Ethyl 3-chloro-1H-indole-2-carboxylate (19.28 mmol, 1.0 equiv.) was dissolved in THF-MeOH—H2O (2:1:1; 85 ml); LiOH.H2O (57.84 mmol, 3.0 equiv.) was added at 0° C. and the mixture was stirred for 12 h at 25° C. The solvent was reduced under reduced pressure, and the residue was taken up in water (50 ml), adjusted to pH 3 with 1 M HCl and extracted with ethyl acetate (2×100 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure, and then the product was crystallized with hexane. Yield: 82%
Reaction SMILES: [N:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][O:3][C:2]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Br[CH2:19][CH:20]([CH3:23])[CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:22][CH2:21][CH:20]([CH3:23])[CH2:19][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[O:3][CH2:4][C:5]3([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[N:1]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(C2=NC3(CCCCC3)CO2)cc1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CCl)COc1ccc(C2=NC3(CCCCC3)CO2)cc1
Yield: 100 %

Procedure:
To a solution of 4-(3-oxa-1-azaspiro[4.5]dec-1-en-2-yl)phenol ax8 (0.5 g, 2.16 mmol, 1 eq) in acetone (30 ml) is added 1-bromo-3-chloro-2-methylpropane (0.25 ml, 2.16 mmol, 1 eq) and potassium carbonate (0.6 g, 4.32 mmol, 2 eq). The mixture is stirred at reflux for 13 days. The mixture is concentrated, taken up in dichloromethane and washed twice with a saturated aqueous solution of ammonium chloride. The organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure to afford 0.7 g of 2-[4-(3-chloro-2-methylpropoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-ene ax64 as a colorless oil. This crude product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH:26]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC.Cl.C([O-])(O)=O.[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH:26]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=3)[CH2:14][CH2:13]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: OC(CCCN1CCN(c2ncc(F)cn2)CC1)(c1ccc(F)cc1)C1CCCCC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A cold (15° C.) solution of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanone (2.1 g, 6.1 mmol) in dry tetrahydrofuran (25 mL) kept under argon atmosphere was treated dropwise (15 min) with a solution of cyclohexylmagnesium chloride in ether (2.0M, 3.18 mL, 6.36 mmol). The cooling bath was removed and reaction mixture after being stirred at 23° C. for 2 h was treated dropwise (15 min) with HCl (2N, 3.5 mL), stirred for 15 min and diluted with CHCl3 (50 mL). The organic phase was basified with NaHCO3 and separated. Aqueous phase was extracted with CHCl3 (15 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to a sticky solid which was purified on silica gel column using a mixture of 40-100% AcOEt in CHCl3 as eluting solvent. The first group of fractions was concentrated in vacuo to give the carbinol as a solid, 1.1 g, 42%. The second group of fractions gave, after evaporation of solvent, the initial ketone 1.0 g, 48%. The carbinol was recrystallized from EtOH to give an analytical sample, mp 53°-9° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@H:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:5]([OH:6])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]>O1CCCC1.O>[CH3:25][C:24]([Si:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH2:9][C@H:7]1[O:8][C@H:3]([CH2:2][NH:1][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:36])[CH2:4][C@@H:5]1[OH:6])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN)C[C@@H]1O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A slurry of 3.15 g of product from Example 283 and 1.35 g of potassium carbonate in 15 ml of tetrahydrofuran at 0° C., under argon, is treated with 2.11 g of p-nitrobenzyl chloroformate and the reaction is stirred vigorously at 0° C. for 4 hours. The reaction mixture is diluted with 100 ml of water, extracted with 3×100 ml of ethyl acetate, dried, concentrated in vacuo and purified by chromatography (Silica Gel: 5-50% ethyl acetate/hexane) to give 3.49 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][CH:12]=[C:11]3[CH2:18][CH2:19]CC(F)(F)F)[CH2:3][CH2:2]1.C(I)C>>[CH2:18]([C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[CH:9]=2)[CH:14]=[N:13][CH:12]=1)[CH3:19]
Reactant: FC(F)(F)CCCc1cncc2ccc(OC3CCNCC3)cc12
Solvent: CCI
Product: CCc1cncc2ccc(OC3CCNCC3)cc12

Procedure:
The compound 266 was synthesized in a similar fashion as described for compound 90, using ethyl iodide. LCMS Method #1, retention time 0.98 min, detected mass 257.31 [M+H]+
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cn2)CC1
Yield: 36.9 %

Procedure:
Tert-butyl piperazine-1-carboxylate (300 mg, 1.611 mmol) and 2-bromo-5-chloropyridine (465 mg, 2.416 mmol) were dissolved in acetonitrile (3 ml), followed by addition of triethylamine (0.45 ml, 3.222 mmol), and then the resulting liquid was subjected to microwave irradiation at 150° C. for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous ammonium chloride solution (10 ml), and extracted with MC (15 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 177 mg of colorless oil (37%).
Reaction SMILES: O[C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.P(Br)(Br)([Br:29])=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1>[Br:29][C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)c(C(=O)Nc3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cnc(Br)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 120.8 %

Procedure:
A solution of 3-hydroxy-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide (84.3 mg, 0.1712 mmol) in toluene (3.000 mL) was treated with POBr3 (196.3 mg, 0.6848 mmol) and the resultant mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and treated with sodium bicarbonate/DCM. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give the impure desired product as a yellow solid (89.4 mg, 95% Yield). MS (ES+) 433.88.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]#[CH:24])[C:10]([NH:12][CH:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:11])=O)(C)(C)C.[ClH:25].O1CCOCC1>C(Cl)Cl>[Cl-:25].[CH3:17][O:16][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[CH:9]([NH3+:8])[CH2:22][C:23]#[CH:24])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: Cl
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C(=O)OC
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CCC([NH3+])C(=O)NC(CC(C)C)C(=O)OC
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of compound 1 (10.55 g: 31 mmol) in DCM (100 mL) was treated with 4M HCl in dioxane (78 mL; 0.31 mol) and stirred at room temperature for 3 h while monitoring the disappearance of the starting material by TLC. The solvent was removed on the rotary evaporator and the residue was treated with ether and then concentrated to give 2 as an off white solid (8.3 g; 96% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[P:7]([O-:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH2:15]=O>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: C=O
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(CN1CCOCC1)OCC
Reaction time: 1 h

Procedure:
To a stirred mixture of morpholine (43.5 g:0.5 mole) and diethyl phosphite (69 g:0.5 mole) was added aqueous formaldehyde (41 g:0.5 mole) during 60 min. at 50°-60°. After stirring for an additional 1 hr. water was removed in vacuo and the resulting oil distilled. Pure diethyl morpholinomethylphosphonate, 105 g (87%) bp 108°-9°/0.1 mm was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:25][CH2:24][C@:12]34[C:13]5[C:14]6[O:23][C@H:11]3[C:10](=O)[CH2:9][CH2:8][C@@:7]4([OH:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]([NH2:22])=[O:21])[CH2:3][CH2:2]1.Cl>C(O)(=O)C.[Zn]>[CH:1]1([CH2:4][N:5]2[CH2:25][CH2:24][C@@:12]34[C:13]5[C:14]([OH:23])=[C:15]([C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:27])[CH2:8][CH2:9][CH2:10][CH2:11]4)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)c1ccc2c(c1O)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CC1)CC3
Temperature: 125 °C
Yield: 29.4 %

Procedure:
To a mixture of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carboxamide [P3] (3.74 g, 10.2 mmol) and zinc powder (33.0 g, 0.51 mol) in acetic acid (220 mL) was added 12N HCl (30 mL). The reaction was heated at 125° C. for 3 hours then allowed to return to room temperature. The mixture was slowly quenched into an ice/water cooled ammonium hydroxide solution at such a rate to ensure the temperature remained below 20° C. The resultant suspension was extracted with DCM (3×500 mL) and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product that was purified by prep-HPLC [Xbridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile Phase A: 10 mM NH4HCO3 (pH 10), Phase B: MeCN; Flow: 50 ml/min; Column Temperature: 30° C.; Runtime: 25 min.] giving 17-(cyclopropylmethyl)-4,14-dihydroxymorphinan-3-carboxamide [13] (1.07 g, 29% yield); LC/MS (r.t. 10.2 minutes [5 to 95% B]), 357 (M+H)+.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C@H:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].[CH3:30]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][CH:26]([CH3:28])[CH2:25][N:29]([CH3:30])[C:3]([CH:5]1[CH2:6][CH2:7][N:8]([C@H:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][CH2:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN([C@H]2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CC(C)CN
Reactant: CN(C)C(On1nnc2cccnc21)=[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)CN(C)C(=O)C1CCN([C@H]2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
tert-butyl (4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.3 g, 0.92 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.14 g, 0.18 mL, 1.84 mmol), HATU (0.53 g, 1.38 mmol) and DIPEA (0.36 g, 0.48 mL, 2.76 mmol) were added. The reaction mixture was stirred at rt for 48 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl (4S)-4-[4-((2-methylpropyl)methylcarbamoyl)piperidin-1-yl]azepane-1-carboxylate (0.12 g, 35%) as a pale yellow gum.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=2)([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)[CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Li+].Cl>O1CCOCC1>[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=2)([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:28][CH:27]=1)=[CH2:30]
Reactant: C=Cc1ccc(C(CC(=O)OC)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=Cc1ccc(C(CC(=O)O)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
Fifty-four (54) mg of methyl 3,3,3-tris(4-vinylphenyl)propionate was suspended in 0.5 ml of dioxane, and to the suspension 0.5 ml of 4N aqueous lithium hydroxide solution was added at room temperature, followed by 17 hours' stirring at 90° C. under heating. The reaction liquid was made acidic by addition of 1N hydrochloric acid, extracted with chloroform and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 52.5 mg of the title compound was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13]>C(N(CC)CC)C>[C:1]([O:21][CH2:20][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CCN(CC)CC
Product: O=C(OC[C@H](OC(=O)c1ccccc1)[C@@H](OC(=O)c1ccccc1)[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OC(=O)c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 74 %

Procedure:
While stirring, 71 parts by weight of benzoyl chloride were dripped over 30 minutes into a mixed solution of 30 parts by weight of sorbitol and 101 parts by weight of triethylamine maintained at 100° C., and the resulting mixture was stirred for an additional 30 minutes. After completion of the reaction, the temperature was lowered to room temperature, and the resulting precipitates were collected by filtration. Thereafter, washing was performed by adding ethyl acetate-pure water. Subsequently, the organic phase was collected and ethyl acetate was distilled out under vacuum, whereby 100 parts by weight (at a yield of 74 percent) of white crystals were obtained. The molecular weight of the resulting compound was 809.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.C(Cl)(Cl)[Cl:30].C(=O)([O-])[O-].[Na+].[Na+].[C:39](Cl)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>O>[C:39]([N:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:27])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([Cl:30])=[O:24])=[CH:25][CH:26]=1)([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid in 200 ml. warm chloroform is added a solution of 15 g. of sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, and evaporated to a viscous, orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[N:3]=[C:4]([I:15])[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: II
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Yield: 54.8 %

Procedure:
To a solution of 2-chloro-5-hydroxypyridine (5 g, from step 11b) and 8.6 g of Na2CO3 in 100 mL of water was added 9.8 g of I2. The mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 5 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystallized from MeOH to afford 5.4 g of the title compound: 1H NMR (CD3OD, 300 MHz) δ 7.09 (d, 1H, J=8.5 Hz), 7.20 (d, 1H, J=8.5 Hz); MS m/z: 256 (M+H)+, 273 (M+NH4)+.