Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N)[CH2:2]CC.[C:6]([N:13]1[CH:17]=[CH:16]N=[CH:14]1)([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7].O>C1COCC1>[CH2:17]([N:13]([CH3:14])[C:6]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7])[CH2:16][CH2:1][CH3:2]
Reactant: CCCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)n1ccnc1

Procedure:
Butylamine (20 g, 0.23 mol) was dissolved in 100 mL of THF and added at a quick dropwise rate to a suspension of carbonyldiimidazole (37.2 g, 0.23 mol) in 200 mL of THF. The solution was headed to reflux for 3 h, then cooled, treated with 200 mL of water, and partitioned into ethyl acetate. The organic layer was separated and then washed with brine, dried with MgSO4, and then concentrated to the crude imidazolide, which was purified by distillation at 108° C. and 600 mtorr to provide a pure oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 3.40 (t, J=7.60 Hz, 2H), 3.06 (s, 3H), 1.61 (m, 2H), 1.31 (m, 2H), 0.93 (t, J=7.23 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:41]3[CH2:42][CH2:43][S:39][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), thiazolidine (57 mg, 0.6 mmol), triethylamine (0.275 g, 2.72 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.544 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concen-trated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH3:12]>C(O)C1C=CC=CC=1>[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:40])=[O:41])=[CH:16][N:15]=1)[C:12]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: OCc1ccccc1
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccc3)[nH]c(=O)c2nn1Cc1ccccn1
Reaction time: 14 h
Yield: 77.7 %

Procedure:
Potassium bis(trimethylsilyl)amide (360 mg, 1.81 mmol) was added to a stirred solution of the title compound of Example 1 (200 mg, 0.36 mmol) in benzyl alcohol (5 ml) at 100° C. and the reaction mixture stirred for 14 hours, then allowed to cool. The resulting mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases separated, the aqueous phase extracted with dichloromethane (2×10 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure. The residual benzyl alcohol was removed by Kugelrohr distillation, then the crude product purified by column chromatography on silica gel, using dichloromethane: methanol (97.5:2.5) as eluant, to provide the title compound (86 mg, 39%) as a white solid. Found: C, 59.92; H, 5.64; N, 17.60. C31H34N8O4S; 0.40 H2O requires C, 59.87; H, 5.64; N, 18.02%. δ (CDCl3): 1.05 (3H,t), 1.29 (3H,t), 2.41 (2H,q), 2.56 (4H,m), 3.05 (2H,q), 3.15 (4H,m), 5.68 (2H,s) 5.75 (2H,s), 7.10 (1H,d), 7.24 (1H,m), 7.42 (3H,m), 7.52 (2H,m), 7.64 (1H,m), 8.58 (1H,d), 8.65 (1H,s), 9.02 (1H,s), 10.58 (1H,s). LRMS: m/z 615 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)N1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(C)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 35 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-isopropylpiperazine to give the title compound in 35% yield; NMR Spectrum: 0.91 (d, 6H), 2.38 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.51-2.56 (m, 1H), 2.76 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.47 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11].O>CO>[CH3:1][O:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(CCCCCBr)N1CCCc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCCC(=O)N1CCCc2ccccc21

Procedure:
Sodium methoxide (0.8 g) was added to a solution of 1-(6-bromohexanoyl)-1,2,3,4-tetrahydroquinoline (2.1 g) in methanol (50 ml). The mixture was refluxed for 8 hours, then poured into water and extracted with ether. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with 98:2 methylene chloride:methanol, so as to obtain the product 1-(6-methoxyhexanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC(O)CCCCCCCCCOCc1ccccc1
Reactant: c1c[nH]cn1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCCCCCOCc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
18-(benzyloxy)octadecan-9-ol (6 g, 15.93 mmol), DMAP (0.195 g, 1.59 mmol) and TEA (2.9 ml, 20.71 mmol) in dry DCM (90 ml) were cooled to 0° C., then methanesulfonyl chloride (1.64 ml) was added under N2. The reaction was warmed to room temperature and stirring continued for another 3 h. The reaction mixture was diluted with DCM (100 ml), washed with 1N HCl, water, and brine solution and dried over MgSO4. The crude compound and imidazole (2.17 g, 31.86 mmol) were then heated at 70° C. for 16 h. The crude product was purified by silica gel column (1.5% MeOH in DCM) to give 1-(18-(benzyloxy)octadecan-9-yl)-1H-imidazole as a gummy liquid (2.22 g, 33%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:15][C:16]1[N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:20](=[O:27])[C:19]([N+:28]([O-:30])=[O:29])=[C:18](OS(C(F)(F)F)(=O)=O)[CH:17]=1.Cl>O1CCCC1>[CH3:15][C:16]1[N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:20](=[O:27])[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C)cc(Sc2ccccc2)c([N+](=O)[O-])c1=O
Reaction time: 0.08 h

Procedure:
1.5 ml (14.6 mmol) of thiophenol are placed in 20 ml of tetrahydrofuran and 2.1 ml (15.1 mmol) of triethylamine are added. 5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4- [[(trifluoromethyl)sulphonyl]-oxy]-1,2-dihydropyridine-1-acetate are added dropwise at room temperature, the mixture is left for 5 minutes at room temperature and then it is poured over 20 ml of a 1 N aqueous hydrochloric acid solution. The reaction medium is extracted with twice 20 ml of dichloromethane, washed with 20 ml of a saturated sodium chloride solution and dried over magnesium sulphate and evaporated to dryness. The residue is washed with ether and it is dried.
Reaction SMILES: [Na].[ClH:2].[N:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6](=[N:12]O)[CH2:5][CH2:4]2.O>C(O)CCCC>[ClH:2].[NH2:12][CH:6]1[CH:7]2[CH2:10][CH2:11][N:3]([CH2:9][CH2:8]2)[CH2:4][CH2:5]1
Reactant: ON=C1CCN2CCC1CC2
Agent: Cl
Agent: [Na]
Solvent: CCCCCO
Solvent: O
Product: NC1CCN2CCC1CC2

Procedure:
Sodium (5.6 g) was added portionwise to a suspension of 1-azabicyclo[3.2.2]nonan-4-one oxime hydrochloride (D1) (2.8 g) in amyl alcohol (100 ml) which was heated under reflux. After all the sodium had reacted, the mixture was cooled to 50° and water (20 ml) was added carefully. The aqueous phase was separated and the amyl alcohol was extracted with 5N hydrochloric acid (2×15 ml). The combined acid extract was washed with diethyl ether and the solvent evaporated in vacuo to give 4-amino-1-azabicyclo[3.2.2]nonane hydrochloride. The hydrochloride salt was basified with 40% sodium hydroxide and the aqueous phase was saturated with potassium carbonate, extracted with diethyl ether, dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (1.4 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9]>ClCCl>[CH2:8]([S:10]([N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH2:3]1)(=[O:12])=[O:11])[CH3:9]
Reactant: Nc1cccnc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N1C=CC=C(N)C1

Procedure:
A solution of 3-aminopyridine (2.15 g, 22.84 mmol) and ethanesulfonyl chloride (2.18 ml, 22.84 mmol) in dichloromethane (150 ml) was stirred for 20 h at room temperature. The mixture was washed with 30 ml saturated sodium bicarbonate solution and extracted with 15% isopropanol/dichloromethane. The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give N-(ethanesulfonyl)-3-aminopyridine (2.15 g, as a crude solid. The solid was dissolved in N,N-dimethylformamide (50 ml) and treated with potassium carbonate (6.37 g, 22.8 mmol) and 3-iodobenzyl bromide (6.80 g, 22.8 mmol) with stirring at room temperature for 3 h. The mixture was diluted with ethyl acetate (150 ml) and washed four times with water (100 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue. The residue was purified on a 200 g pad of silica eluting with 3% methanol/dichloromethane to afford the title compound. MS calcd. 402.3; MS (M+1) 403.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Br:11])=[CH:9][N:8]=[C:7](SC)[N:6]=1)=[O:4].ClC1C=CC=C(C(OO)=O)C=1.Cl.CN.C[CH2:29][N:30](C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[Br:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([NH:30][CH3:29])=[N:8][CH:9]=1
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1ncc(Br)c(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Methyl-5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1.0 eq, 661 mg, 2.52 mmol) was dissolved in CH2Cl2 (10 ml). meta-chloro perbenzoic acid (m-cpba, 77% pure grade, 2.5 eq, 1.42 g, 6.34 mmol) was added and the mixture was stirred at room temperature for 1 hour. To the resulting suspension was added anhydrous THF (10 ml), methylamine hydrochloride (10 eq, 1.7 g, 25.18 mmol) and DIEA (10 eq, 4.3 ml, 24.69 mmol) and the mixture stirred at room temperature overnight. The solvents were removed in vacuo prior to adding CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The two phases were decanted and two further CH2Cl2 extractions were carried out. The combined extracts were dried over Na2SO4 and the solvents evaporated. Purification by flash chromatography on silica gel (20-30% ethylacetate in hexanes) provided methyl 5-bromo-2-(methylamino)pyrimidine-4-carboxylate as an off-white solid (461 mg, 75% yield). LCMS (ES): >95% pure, m/z 246 [M]+, 248 [M+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][CH3:17])[C:10]([O:18][CH3:19])=[C:9]2[C:4]=1[CH:5]1[CH2:20][CH:8]2[CH:7]=[CH:6]1.O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].Cl.CN(C)CCCN=C=NCC>ClCCl>[O:28]=[C:23]1[CH2:24][CH2:25][C:26](=[O:27])[N:22]1[O:14][C:13]([C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[C:10]([O:18][CH3:19])[C:11]=1[O:16][CH3:17])[CH:8]1[CH2:20][CH:5]2[CH:6]=[CH:7]1)=[O:15]
Reactant: COc1c(OC)c2c(c(OC)c1C(=O)O)C1C=CC2C1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(OC)c2c(c(OC)c1C(=O)ON1C(=O)CCC1=O)C1C=CC2C1
Reaction time: 15 h
Yield: 68.3 %

Procedure:
To a solution of 15 (0.972 g, 3.52 mmol) in dichloromethane (80 mL) was added N-hydroxysuccinimide (0.547 g, 4.75 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.890 g, 4.64 mmol), and the resulting reaction mixture was stirred under dinitrogen for 15 h. The reaction mixture was diluted with dichloromethane (100 mL), washed twice with a 0.01 N HCl solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification was performed using silica gel chromatography (dichloromethane→2:1 ethyl acetate/hexanes) to yield 0.898 g (68%) of 3 as a colorless sticky solid. 1H NMR (300 MHz, CDCl3): δ=2.19-2.27 (m, 2H, CH—CH2—CH), 2.89 (bs, 4H, CH2—CH2), 3.86 (s, 3H, O—CH3), 3.92 (s, 3H, O—CH3), 3.95 (s, 3H, O—CH3), 4.19-4.23 (m, 2H, CH—CH(C)—CH2), 6.78-6.85 (m, 2H, HC═CH); 13C NMR (75 MHz, CDCl3): δ=25.9 (CH2—CH2), 47.7 (CH—CH(C)—CH2), 47.9 (CH—CH(C)—CH2), 61.7 (O—CH3), 62.3 (O—CH3), 62.6 (O—CH3), 68.6 (CH—CH2—CH), 137.7, 142.4 (CH═CH), 143.0 (CH═CH), 144.2, 147.9, 149.6, 149.9, 161.4, 169.1; TLC: Rf=0.42 (2:1 ethyl acetate/hexanes); ESI-MS calcd for C19H19NO7 [M+Na]+: 396.1059. found 396.1069.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([CH3:30])[NH:24]2>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:28]1[C:20]([F:19])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:30])=[CH:22]2)#[N:13]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1C#N
Yield: 57.2 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (200 mg, 0.76 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (150 mg, 0.91 mmol), (prepared as described for the starting material in Example 11), in DMF (6 ml) to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(2-methoxyethoxy)quinoline (170 mg, 57%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52]C)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=4)[CH2:27][CH:26]3[CH2:44][N:51]([CH3:52])[CH3:49])=[O:24])=[CH:18][C:17]=2[CH:46]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CN(C)C)=C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of oxalyl chloride (175 mg) in methylene chloride (1 ml) is added dropwise at -78° C. a solution of dimethyl sulfoxide (215 mg) in methylene chloride (1 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added triethylamine (650 mg), then the reaction temperature is raised up to room temperature. To the reaction mixture is then added water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (5 ml). To the mixture are added dimethylamine hydrochloride (200 mg) and sodium cyanoborohydride (130 mg). The reaction mixture is stirred for 48 hours at room temperature and then poured into a 1N NaOH solution, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:methanol ethyl acetate=15:85) to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-dimethylaminomethyl-4-(3,4,5-trimethoxybenzyl) piperazine (200 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 167-169° C.
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[CH3:22][NH2:23]>C(Cl)Cl.CCO>[CH3:22][NH:23][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CN
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CNC(C)c1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (50 mg, 122 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with MeNH2 (153 μL of a 8 M solution in EtOH, 1.22 mmol) at rt for 2 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 22-52% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (13.2 mg, 12% over two steps). MS (ESI+) for C17H18N2O2S m/z 284 (M-NHMe)+, 315 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=[O:12]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 1,8-naphthalic anhydride (25 g, 0.13 mol) in conc. H2SO4 (100 mL) was added dropwise a solution of conc. HNO3 (7.85 g, 0.13 mol) in conc. H2SO4 (25 mL) at 0° C. After the addition was complete, the resulting mixture was allowed to warm to RT, stirred for 90 min and then poured into ice-H2O. The solid was filtered by suction, washed with H2O, and re-crystallized from glacial AcOH to yield 3-nitro-1,8-naphthalic anhydride (24.5 g). 1H NMR (300 MHz, CDCl3): δ 9.11 (s, 1H), 9.06 (s, 1H), 8.58 (d, J=7.5 Hz, 1H), 8.43 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14]C4CC4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.COC1C=CC2C[C@H]3NCC[C@]45[C@H](C(CC[C@@]34O)=O)OC=1C=25.[CH3:48][O:49][C:50]1[CH:73]=[CH:72][C:53]2[CH2:54][C@H:55]3[N:60]([CH2:61]C4CC4)[CH2:59][CH2:58][C@:57]45[C@H:65]([C:67]([CH2:69][CH2:70][C@@:56]34[OH:71])=[O:68])[O:66][C:51]=1[C:52]=25.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(CC[C@]2(O)[C@]5(C=34)CC1)=O.CN1[C@@H]2CC3C=CC(O)=C4O[C@H]5C(C=C[C@]2(O)[C@]5(C=34)CC1)=O>>[CH3:61][N:60]1[C@@H:55]2[CH2:54][C:53]3[CH:72]=[CH:73][C:50]([O:49][CH3:48])=[C:51]4[O:66][C@H:65]5[C:67]([CH2:69][CH2:70][C@:56]2([OH:71])[C@:57]5([C:52]=34)[CH2:58][CH2:59]1)=[O:68].[CH3:14][N:13]1[C@@H:8]2[CH2:7][C:6]3=[CH:1][CH:2]=[C:3]([OH:25])[C:4]4[O:19][C@H:18]5[C:20]([CH2:22][CH2:23][C@:9]2([OH:24])[C@:10]5([C:5]=43)[CH2:11][CH2:12]1)=[O:21]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)NCC[C@]314
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5

Procedure:
It has been our surprising finding that making naltrexone via noroxycodone and N-cyclopropylmethylnoroxycodone is more efficient (circa 54% overall from oxycodone) than proceeding via noroxymorphone to naltrexone even when produced by the novel procedures of the present invention (43% overall from oxycodone via oxymorphone). Both procedures are more than twice as efficient as the procedures of the art which produce noroxymorphone from oxycodone via oxymorphone (Seki, Takamine Kenkyusho Nempo, 12, 56 (1960)), which proceed in an overall yield of about 21%. A third procedure for the synthesis of naltrexone is set forth in Applicant's co-pending application filed concurrently herewith.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH2:17][OH:18]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:16][CH2:17][OH:18])[C:4](=[O:8])[CH:3]=1
Reactant: OCCI
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(Br)ccn1CCO
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.8 %

Procedure:
To a solution of 4-bromopyridin-2(1H)-one (174 mg, 1.00 mmol) in THF (3.5 mL) was added K2CO3 (1.38 g, 10.0 mmol) and 2-iodoethanol (156 μL, 2.00 mmol). The reaction was stirred at 80° C. for 2 days before being cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (0-10% MeOH—CH2Cl2) to yield 4-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one as a pale yellow solid (30 mg, 7%). ESI-MS m/z calc. 217.0. found 218.3 (M+1)+. Retention time 0.33 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=7.2 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 6.44 (dd, J=2.2, 7.2 Hz, 1H), 4.89 (t, J=5.4 Hz, 1H), 3.91 (t, J=5.4 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H).