Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])C1C2C(=CC=CC=2)C=CC=1.COC1C=C(C=CC=1)C(O)[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Reactant: COc1cccc(C(O)c2ccc3ccccc3c2)c1
Product: COc1cccc(C(Cl)c2ccc3ccccc3c2)c1

Procedure:
The compound 7 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 6.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:42]([O:41][C:33]1[CH:32]=[C:31]([C:23]2[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:26]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:22]=2)[CH:36]=[CH:35][C:34]=1[C:37]([F:40])([F:39])[F:38])[CH3:43]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-(3-ethoxy-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 72%). MS (ISP) 569.2 [(M+H)+]; mp 223.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(Cl)ccc43)c2cc1OC
Yield: 92 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 92% yield from 5-chloro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 190°14 191° C.; GC/MS: 3.41 (M+); anal. RP18-HPLC RT: 4.58 min.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=O)[C:12]=12)=[O:15].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]([CH2:14][OH:15])[C:12]=1[CH2:17][OH:16]
Reactant: COCOc1cccc2c1C(=O)OC2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1cccc(CO)c1CO
Temperature: 0 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
After that, lithium aluminum hydride (1.14 g, 30.0 mmol) was added little by little to a solution of 3-methoxymethyloxyphthalic anhydride (3.0 g, 14.4 mmol) in anhydrous tetrahydrofuran (100 ml) under cooling with ice water and the mixture was returned to room temperature followed by stirring for 12 hours. The reaction solution was diluted with ether (300 ml) and a saturated aqueous solution (3 ml) of ammonium chloride was added thereto followed by stirring for 1 hour. The reaction solution was dried over anhydrous magnesium sulfate, filtered off through celite and the filtrate was concentrated to provide 1.71 g (yield 60%) of 3-methoxymethyloxy-1,2-benzenedimethanol as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[C:20]([O:24][C:25]([NH:27][NH2:28])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25]([N:27]1[C:15](=[O:17])[C:3]2[CH:4]=[N:5][C:6]3[C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1[nH]c2c(cnc3c([N+](=O)[O-])cccc32)c1=O
Yield: 77.8 %

Procedure:
A mixture of 4-chloro-3-ethoxycarbonyl-8-nitroquinoline (500 mg) and tert-butoxycarbonylhydrazine (283 mg) in dioxane was refluxed for 1 hour. The mixture was concentrated in vacuo to give 2-tert-butoxycarbonyl-2,3-dihydro-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (458 mg).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([NH:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Benzyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give 1-benzyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 88%) as a white solid: mp 304-306° C., 1H NMR (DMSO-d6) δ 1.97-2.02 (m, 1H), 2.30-2.34 (m, 1H), 2.50-2.65 (m, 1H), 2.85-2.98 (m, 1H), 4.21-4.52 (m, 6H), 5.09-5.16 (dd, J=4.5 and 13.0 Hz, 1H, CH), 6.51-6.53 (m, 2H), 7.23-7.61 (m, 8H), 11.01 (s, 1H), 13C NMR (DMSO-d6) δ 22.56, 31.18, 40.01, 42.96, 46.14, 51.52, 121.38, 126.52, 126.95, 128.17, 130.23, 131.60, 136.11, 139.80, 140.78, 157.95, 168.09, 170.95, 172.82; Anal. calcd. for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C, 64.90; H, 5.53; N, 13.46.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[N:16]=[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[N:16]1[C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=12
Reactant: CC(C)(C)OC(=O)Nc1nc2cnccn2n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc2n(n1)CCNC2
Temperature: 60 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
A 100-mL round-bottomed flask was purged with nitrogen and charged with 270c (1.0 g, 4.25 mmol), 20% palladium on carbon (10% wet, 200 mg), and ethanol (40 mL). It was then evacuated, charged with hydrogen gas (25 atm), and stirred at 60° C. for 24 h. The hydrogen was evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 270d (700 mg, 68%). MS-ESI: [M-t-Bu]+ 184.0
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=[C:11]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1=NNC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of ethyl 1,4-dihydro-4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (0.4 g) in chloroform (6 ml) was added activated manganese dioxide (2 g) and the mixture was refluxed for 30 minutes with stirring vigorously. After allowing to cool to ambient temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo, and the residual precipitate was recrystallized from diethyl ether. The crystal was collected by filtration, washed with diethyl ether and dried in vacuo to give ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (0.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:9])[CH2:15][CH2:14]1)[CH3:34]
Reactant: CCOC(=O)CCCCCCBr
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 87 %

Procedure:
This compound was prepared according to the procedure used in Example 7. A mixture of 4.6 g (0.015 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of ethyl 7-bromoheptanoate, 6.4 g (0.061 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 50 ml of N,N-dimethylformamide gave 6.0 g of a dark oil. The oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPAK® 500/silica; ethyl acetate; flow rate 150 ml/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 2.5 g (44%) of a viscous, yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]1[CH:11]=[CH:12][N:13]2[C:18]([CH:19]=1)=[C:17]([CH2:20][CH3:21])[C:16]1[S:22][NH:23][C:24](=[O:25])[C:15]=1[C:14]2=[O:26]>CS(C)=O>[CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([CH:19]=2)=[C:17]([CH2:20][CH3:21])[C:16]2[S:22][NH:23][C:24](=[O:25])[C:15]=2[C:14]3=[O:26])[CH2:4]1
Reactant: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(Cl)cc12
Reactant: CN(C)C1CCNC1
Solvent: CS(C)=O
Product: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(N3CCC(N(C)C)C3)cc12

Procedure:
(rac)-3-(Dimethylamino)pyrrolidine (30.0 μL, 0.239 mmol) is added to a yellow solution of 6 (11.4 mg, 0.041 mmol) in dimethyl sulfoxide (0.6 ml) at room temperature to give immediately an orange mixture. This mixture is irradiated in a microwave for 5 min. (120° C.; 300 W) to give an orange solution. The solution is evaporated under reduced pressure (˜1 mm Hg, 60° C.), and the remaining orange solid is washed with diethyl ether (3×15 mL) and water (3×15 mL). Subsequent drying in vacuo yields 7 as a yellow solid. Purity by HPLC: 97%; tR=10.86 min. mp 217–219° C. 1H NMR (DMSO-d6): δ1.11 (br t, J=6.5 Hz, 3H, CH2CH3), 1.85 (m, 1H, pyrrolidinyl H-4), 2.19 (m, 1H, pyrrolidinyl H-4′), 2.22 (s, 6H, N(CH3)2), 2.55 (br, 2H, CH2CH3), 2.84 (m, 1H, pyrrolidinyl H-3), 3.26 (m, 1H, pyrrolidinyl H-2), 3.44 (m, 1H, pyrrolidinyl H-5), 3.67 (m, 2H, overlapping pyrrolidinyl H-2′ and pyrrolidinyl H-5′), 6.14 (br, 1H, pyridone H-8), 6.84 (br d, J=8.0 Hz, 1H, pyridone H-6), 8.86 (d, J=8.0 Hz, 1H, pyridone H-5). 13C{1H} NMR (DMSO-d6): δ12.1 (CH2CH3), 21.8 (CH2CH3), 29.1 (pyrrolidinyl C-4), 43.8 (N(CH3)2), 46.9 (pyrrolidinyl C-5), 51.8 (pyrrolidinyl C-2), 64.6 (pyrrolidinyl C-3), 92.5 (C-8, CH), 95.7 (C-3a), 99.9 (C-9), 105.9 (C-6, CH), 129.3 (C-5, CH), 141.8 (C-8a), 148.3 (C-7, C—N), 153.3 (C-4, NC(O)), 154.9 (C-9a, C—S), 167.9 (C-3, CONS). LCMS m/z calcd for C18H22N4O2S 358 ([M+]); found 359 ([M+H]+). HRMS m/z calcd for C18H22N4NaO2S 381.1361 ([M+Na]+); found 381.1366. Anal. Calcd. for C18H22N4O2S.H2O: C, 57.43; H, 6.43; N, 14.88. Found: C, 57.29; H, 6.08; N, 14.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[CH2:17]([O:19][C:20](=[O:38])[CH:21](P(OCC)(OCC)=O)[CH2:22][CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1)[CH3:18].O.[OH-].[Li+].O>C1COCC1.C(O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:38])/[C:21](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH2:22][CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1)[CH3:18]
Reactant: CCOC(=O)C(CCCC1OCCO1)P(=O)(OCC)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCC1OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-benzaldehyde (580 mg) obtained in Example 1 in THF (10 mL) and ethanol (10 mL), 2-(diethoxyphosphoryl)-5-[1,3]dioxolan-2-yl valeric acid ethyl ester (826 mg) and lithium hydroxide monohydrate (205 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:ethyl acetate→ethyl acetate:ethanol=20:1), and it was obtained 485 mg, the title compound was obtained as an isomer mixture (E:Z=4:1). The physical properties of the compound are as follows.
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: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
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:3]=[C:4]2[C:15]3([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:18]=4[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.C(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:18]=4[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Agent: O=C=O
Product: NC1=N[C@@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21

Procedure:
7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine (483 mg) was subjected to chromatography using supercritical CO2 (additives 35% MeOH with 20 mM NH3) on a ChiralPak ADH (21×250 mm, 5 μm) eluting at a flow rate 65 ml/min (100 bar pressure, 40° C. column temperature). The first peak (retention time=1.8 min) provided (R)-7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine (Example 14c-1, >99% ee), and the second peak (retention time=3.5 min) provided (S)-7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine (Example 14c-2, >99% ee).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH2:6][OH:7])[CH2:4][OH:5].CO[C:17](OC)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.C(OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[OH:1][CH2:2][C:3]1([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:6][O:7][C:17]([CH3:19])([CH3:18])[O:5][CH2:4]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)C(=O)NC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CO)(NC(=O)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
A solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (15.7 g, 130 mmol) and di-tert-butyl dicarbonate (31.1 g, 143 mmol) in methanol (400 mL) and water (40 mL) was stirred at ambient temperature for 72 h. The contents of the flask were evaporated and the resulting white solid dissolved in minimal hot ethyl acetate and allowed to recrystallise overnight. The crystals were filtered and washed with petroleum ether to give N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)pivalamide (26.5 g, 130 mmol, 100%) as fluffy, white needles. To a solution of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)pivalamide (9.50 g, 42.0 mmol) and 2,2-dimethoxypropane (16.0 mL, 129 mmol) in DMF (100 mL) was added pyridinium para-toluenesulfonate (0.540 g, 2.15 mmol) at RT. The reaction was stirred at ambient temperature for 15 h. after which time the reaction was complete by TLC (petroleum ether:ethyl acetate, 4:1, visualised with Erlichs). The reaction mixture was diluted with diethyl ether, washed three times with aqueous sodium bicarbonate, once with brine, dried over magnesium sulphate, filtered and evaporated. The resulting semi-solid was recrystallised from minimal hot petroleum ether to give N-(5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)pivalamide (7.32 g, 65%) as white crystals. 1H NMR (CDCl3) δ 5.31 (br s, 1H, NH), 4.18 (br s, 1H, OH), 3.85 (d, J=11.5 Hz, 2H), 3.80 (d, J=11.5 Hz, 2H), 3.70 (d, 6.6 Hz, 2H), 1.46 (s, 12H), 1.44 (s, 3H). 13C NMR (CDCl3) δ 154.0, 98.8, 80.5, 64.8, 64.5 (2C), 53.4, 28.3 (3C), 26.9, 20.3.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11](CC4C=CC(OC)=C(OC)C=4)[CH:8]3[N:9]=2)=[C:5]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[N:4]=[CH:3]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[NH:11][CH:8]3[N:9]=2)=[C:5]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[N:4]=[CH:3]1
Reactant: COc1ccc(CN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CN1C(=O)NC2N=C3C(=C(c4ccco4)N=CN3N)N21
Temperature: 160 °C
Yield: 38.6 %

Procedure:
A mixture of 5-amino-3-[(3,4-dimethoxyphenyl)methyl]-8-(2-furyl)-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (0.1 g, 0.237 mmol), 1,2-dichlorobenzene (5 ml), and aluminium chloride (0.095 g, 0.711 mmol) were stirred at and heated at 160° C. for 45 minutes. Reaction mixture was cooled to room temperature and purified by LCMS to obtain pure 5-amino-8-(2-furyl)-1-methyl-3H-[1,2,4]triazolo[5,1-f]purin-2-one (0.025 g, 39%).
Reaction SMILES: C([N:8]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH:9]1[CH2:22][OH:23])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH2:13][CH:12]1[NH:8][CH:9]([CH2:22][OH:23])[CH2:10][CH2:11]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (6.3 g) in methanol (63 ml) was added palladium hydroxide on carbon (630 mg) under nitrogen atmosphere. The apparatus was evacuated to remove nitrogen, then filled with hydrogen, and the mixture was stirred under hydrogen atmosphere until 19 mmol of hydrogen was absorbed. The palladium hydroxide on carbon was filtered off and the solvent was removed under reduced pressure to give 5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.0 g). To a solution of this residue in tetrahydrofuran (60 ml) and water (30 ml) were added sodium bicarbonate (4.10 g) and then allyl chloroformate (1.42 ml) at room temperature. After stirring for 2 hours, sodium bicarbonate (2.1 g) and allyloxycarbonyl chloride (1.42 ml) was added. After stirring for an hour, ethyl acetate (100 ml) and water (50 ml) were added and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:hexane/ethyl acetate, 9:1-4:1 V/V) to give 1-allyloxycarbonyl-5-t- butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.91 g).
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:14]=1.C(N)CC.C1C=CC2N(O)N=NC=2C=1>CC#N.CCOC(C)=O>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([NH:5][CH2:6][CH2:7][CH3:8])=[O:22])[CH:14]=1
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCN
Product: CCCNC(=O)Cc1cccc(-c2ccccc2)c1
Reaction time: 72 h

Procedure:
EDAC.HCl (114 mg, 0.59 mmol) was added to a mixture of compound 91C (125 mg, 0.59 mmol), propylamine (49 μL, 0.59 mmol) and HOBT (80 mg, 0.59 mmol) in 1 mL of CH3CN. The reaction was stirred for 72 hours. After this time, the mixture was diluted with AcOEt. The organic layer was washed three times with HCl 2N, three times with NaOH 2N, dried over MgSO4 and concentrated. A with solid was obtained (100 mg, 67%). NMR 1H (ppm, CDCl3): 7.57 (d., J3=7.05 Hz, 2H), 7.52-7.32 (m, 6H), 7.23 J3=7.94 Hz, 1H), 5.65 (br. s., 1H), 3.62 (s, 2H), 3.20-3.13 (m, 2H), 1.44 (sex. J3=7.21 Hz, 2H), 0.83 (t, J3=7.43 Hz, 3H). NMR 13C (ppm, CDCl3): 170.9, 141.9, 140.5, 135.5, 129.3, 128.8, 128.2, 127.5, 127.0, 126.0, 43.8, 41.3, 22.7, 11.2. MS (+ESI): M+H+: 254.3.