Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[Cl:41]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=[CH:33][C:32]=3[Cl:41])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3cc(C(F)(F)F)ccc3Cl)CC2=O)CCCCC1)c1cc2ccccc2s1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 222 mg of the titled compound was prepared
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:41]=[CH:42][CH:43]=2)[C:22]([C:24]2[C:34](C3C=CC=CC=3)=CC=C[C:25]=2[NH:26]C(=C)C#N)=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:34][C:24]=1[C:22](=[O:23])[C:21]1[CH:41]=[CH:42][CH:43]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: C=C(C#N)Nc1cccc(-c2ccccc2)c1C(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylamlinoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2-3%MeOH/CH2Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[CH:14]=[C:15](F)[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[O:28]1[C:30]2([CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]2)[CH2:29]1>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:29][C:30]4([OH:28])[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 72 °C
Yield: 60.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.065 g, 0.25 mmol), cesium carbonate (0.16 g, 0.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.6]nonane-6-carboxylate (0.068 g, 0.30 mmol) were added to 1 mL of DMF and heated to 72° C. overnight. The reaction mixture was concentrated, and DCM was added to the residue. Solids were removed by filtration and the filtrate was purified on Silica gel using 6% NH4OH in MeOH and DCM to yield 74 mg of the desired product as an off-white foam. MS ESI (+) m/z 490 (M+1) detected.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[Mg]Br>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:28]3[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=3[CH3:26])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1ccc(C)c([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 2,5-dimethylphenylmagnesium bromide. Yield: 57 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC#N)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCC(N)=O)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile (2.0 g, 5.17 mmol) and conc. sulfuric acid (20 ml) was stirred at RT for 17 h, poured into 150 ml ice/water and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water (100 ml), dried (MgSO4) and evaporated to give the title compound as a white foam, MS: m/e=404 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[C:23]([O-])(=[O:25])[CH3:24].[Na+]>C(OC(=O)C)(=O)C>[C:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.00 g, 3.39 mmol), sodium acetate (0.556 g, 6.78 mmol) and acetic anhydride (20 mL) was heated at reflux for 0.5 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated in vacuo. Trituration of the residue in water (20 mL), followed by recrystallization of the resultant solid from hexanes/diethyl ether, afforded 1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.802 g, 70%) as a colorless solid: mp 236-238° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.32-8.25 (m, 1H), 7.42-7.33 (m, 1H), 7.25-7.15 (m, 2H), 6.52 (s, 1H), 6.25 (s, 1H), 4.97-4.90 (m, 1H), 4.68-4.60 (m, 1H), 4.25-4.04 (m, 4H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.5, 171.0, 155.2, 145.1, 139.6, 138.6, 130.8, 129.4, 126.2, 123.7, 121.0, 116.8, 111.7, 99.6, 80.9, 64.6, 64.0, 58.8, 26.7; MS (ES+) m/z 360.1 (M+23).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].O.Cl>N1C=CC=CC=1>[CH3:9][S:10]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)(=[O:12])=[O:11]
Reactant: Nc1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 72 h
Yield: 23.1 %

Procedure:
5.4 g (49.5 mmol) of p-aminophenol are dissolved in 40 ml of anhydrous pyridine, and 5.7 g (1 equivalent) of methanesulfonyl chloride diluted in 12 ml of pyridine are added over 15 minutes at 20° C. under a stream of nitrogen. The reaction medium is stirred for 3 days at 20° C. and is then poured into 1.5 liters of water containing a sufficient amount of hydrochloric acid (67 g of 36% HCl) to neutralize the pyridine and to establish a pH≦1.5. The aqueous phase is separated out by settling and extracted twice with 250 ml of ethyl acetate. The organic phases are combined and washed with twice 250 ml of water and then concentrated under vacuum. The residue is recrystallized from 40 ml of ethyl acetate. The crystals are filtered off at 0° C. and washed with 15 ml of ethyl acetate. 2.14 g of crude p-methanesulfonamidophenol are obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:33][CH3:34])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:9][CH:8]1[F:32]>CN(C)C=O>[CH3:34][O:33][C:7]1([O:6][CH3:5])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:9][CH:8]1[F:32]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)CC1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1F
Temperature: 70 °C
Yield: 78 %

Procedure:
The mixture of sodium azide (67.0 mmol) and (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (27.0 mmol) in dimethylformamide was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 78% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(F)cc3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58.2 mg), 5-fluoro-2-hydroxyacetophenone (409 mg), and 4-dimethylaminopyridine (317 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 8 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (63.5 mg, yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:20]3[N:28](S(C4C=CC(C)=CC=4)(=O)=O)[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[CH:21]=3)=[CH:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]2=[CH:5][C:4]=1[O:39][CH3:40].CO>[OH-].[K+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[CH:21]=3)=[CH:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]2=[CH:5][C:4]=1[O:39][CH3:40]
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3[nH]1)cn2CCN1CCOCC1
Temperature: 55 °C
Yield: 56.5 %

Procedure:
Bring bisazaindole 19 (48 mg, 0.0856 mmol) to reflux in KOH at 3%/MeOH for 8 h, then continue heating at 55° C. for 16 h. The reaction medium is then concentrated under vacuum, the residue is diluted with EtOAc, washed with saturated NaHCO3, dried (MgSO4), and concentrated until a residual oil is obtained. The latter is submitted to flash chromatography to give 20 (19.7 mg, 56.6%) as a white solid: 1H NMR (CDCl3) δ 10.77 (s broad, 1H), 8.20 (d, 1H, J=4.5 Hz), 7.82 (d, 1H, J=7.5 Hz), 7.57 (s, 1H), 7.13 (s, 1H), 7.03 (m, 1H), 6.57 (d, 1H, J=1.5 Hz), 4.23 (s, 3H), 4.22 (t, 2H, J=6.6 Hz), 3.96 (s, 3H), 3.70 (t, 4H, J=4.6 Hz), 2.77 (t, 2H, J=6.4 Hz), 2.49 (t, 4H, J=4.6 Hz). TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.20, m/z obs.=408.26 (M+1).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)O
Reactant: OCC1=CCCCC1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1=CCCCC1
Yield: 78 %

Procedure:
CHMA was prepared by the above procedure from cyclohexenyl methanol (200 grams, 1.79 mole), methacrylic acid (137.6 grams, 1.60 mole), p-toluenesulfonic acid (15.2 grams, 80 mmole), MEHQ (8 grams, 5.7 mmole), and toluene (1000 ml) in a 2 liter reaction flask. The aqueous washes were performed with 400 ml portions for each wash. The CHMA was obtained in an amount of 225.9 grams (78% yield). The CHMA was determined to have a boiling point in the range of 64-66° C. at a reduced pressure of 0.3 Torr.
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][C:8]1[C:13]([C:14]#[C:15][Si](C)(C)C)=[CH:12][CH:11]=[CH:10][C:9]=1[O:20][C:21]([F:24])([F:23])[F:22])C>C(O)(C)(C)C>[F:22][C:21]([F:24])([F:23])[O:20][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][CH:15]=[CH:14]2
Reactant: CCOC(=O)Nc1c(C#C[Si](C)(C)C)cccc1OC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: FC(F)(F)Oc1cccc2cc[nH]c12
Reaction time: 2 h
Yield: 103.3 %

Procedure:
Potassium hydroxide (17.9 g, 321 mmol) was boiled for 2 h in t-butanol (500 mL). (2-Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (52.8 g, 153 mmol) dissolved in t-butanol (500 mL) was added and boiling was continued for 2 h. The solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 31.8 g of a brownish oil, which was purified by chromatography on silica gel with hexane/ethylacetate (9:1). This yielded the title compound, (30.2 g, 98%) as a yellow oil. (EI-MS: m/e=201.0 (M+))
Reaction SMILES: C(=O)([O-])O.[Na+].[NH:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:8][CH2:7]1.CS(O[CH2:32][CH2:33][C@:34]1([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)[O:38][CH2:37][N:36]([C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)[CH2:35]1)(=O)=O>C(#N)C>[F:52][C:50]([F:51])([F:53])[C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=1)[C:39]([N:36]1[CH2:35][C@@:34]([CH2:33][CH2:32][N:6]2[CH2:11][CH2:10][C:9]3([C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C@@H:12]3[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:8][CH2:7]2)([C:55]2[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=2)[O:38][CH2:37]1)=[O:54]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Reactant: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCNCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Sodium hydrogencarbonate (7.15 g, 85.11 mmol) was added to a solution of the crude product (32.1 g) obtained in Example 1h and the compound (37.6 g, 70.9 mmol) obtained in Example 1d in acetonitrile (160 mL) with stirring at room temperature, and the mixture was stirred at reflux temperature under a nitrogen atmosphere for 14 hours. The reaction mixture was left to stand for cooling to room temperature, and then the organic solvent was evaporated under reduced pressure. An aqueous sodium hydrogencarbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1→0:1, v/v) to give the title compound (47.8 g; yield, 93%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.56 g, 0.008 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.90 g, 0.038 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (2.40 g, 0.008 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (910 mg, 29%) as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].O>C(O)C.C(O)(CC)(C)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Solvent: CCO
Solvent: CCC(C)(C)O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Temperature: 82.5 °C

Procedure:
Crude oxymorphone, which contains residual water and, in some instances, can also contain residual ethanol, is dissolved in tert-amyl alcohol and the solution dried to remove water. This oxymorphone solution is then treated with excess allyl chloroformate (compound (102)) and sodium bicarbonate at 70-85° C. (Step 3). Once the reaction is complete (i.e., conversion of oxymorphone to the 3-allylcarbonate-N-allylcarbamate noroxymorphone (compound (109)), in which none, some, or all of the 14-OH can also be converted to a 14-allylcarbonate group (i.e., compound (110)), water and sodium carbonate are added and, in Step 4A, the mixture is heated to 80-85° C. for at least 15 hours to destroy excess allyl chloroformate and to hydrolyze the 3-carbonate moiety as well as any 14-carbonate groups that might be present, providing the 17-allylcarbamate derivative of noroxymorphone (compound (105)). The product, noroxymorphone-17-allylcarbamate, can be extracted into a suitable organic solvent which can be filtered, washed, and dried using normal work-up procedures. If desired, the product can be recovered by evaporation of that solvent.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([S:12]([NH:15][C:16]([NH:18][C:19]2[N:24]=[C:23]([C:25](OC)=[O:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[O:17])(=[O:14])=[O:13])=[CH:9][C:8]=1[CH3:33])(=O)C.[BH4-].[Li+]>O1CCCC1>[OH:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([S:12]([NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=[C:23]([CH2:25][OH:26])[N:24]=2)(=[O:14])=[O:13])=[CH:9][C:8]=1[CH3:33]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC(=O)NS(=O)(=O)c2cc(C)c(CCOC(C)=O)s2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)cc(CO)n2)sc1CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.100 g methyl 6-[({[5-(2-acetoxyethyl)-4-methyl-2-thienyl]sulfonyl}carbamoyl)amino]-4-(trifluoromethyl)pyridine-2-carboxylate in 1.5 ml tetrahydrofuran was added 0.02 g lithiumborohydride and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated. The organic phase was washed with water. To he combined water phases was added 1 ml 10% citric acid and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and evaporated to yield the title compound as white foam (containing acetoxy and hydroxyethyl ca 1:1) The mixture was dissolved in ca 2 ml methanol and ca 0.05 ml 28% sodium hydroxide and kept at room temperature for 5 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated to yield 0.049 g of the title compound as white foam. MS (ISN) M−H+=438.4
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1.[F:17]C1C=CC(C2C=CC(CO)=CC=2OC)=CC=1>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1
Reactant: COc1cc(CCl)ccc1-c1ccccc1
Reactant: COc1cc(CO)ccc1-c1ccc(F)cc1
Product: COc1cc(CCl)ccc1-c1ccc(F)cc1

Procedure:
Following the same procedure for the preparation of 4-Chloromethyl-2-methoxy-biphenyl, the title compound is prepared from (4′-Fluoro-2-methoxy-biphenyl-4-yl)-methanol (crude material from the previous step). The crude material is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:29]([N:31]([C@@H:43]([CH3:51])[CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:29]([N:31]([C@@H:43]([CH3:51])[CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 89 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.