Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.C1COCC1.[BH3-]C#N.[Na+]>CO.Cl[Ti](Cl)(Cl)Cl>[C:22]1([CH3:21])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:23]=1
Reactant: Cc1cccc(CCN)c1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(CCNC2CCc3cc(Oc4ccc(C(N)=O)cn4)ccc32)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
Add Ti(iPrO)4 (1.70 g, 6.00 mmol) to a suspension of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(3-methylphenyl)ethylamine (446 mg, 3.30 mmol) and THF (20 ml) and stir for six hours under a nitrogen atmosphere at ambient temperature. After cooling in an ice/water bath, treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at 0-5° C. for two hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). Allow the reaction mixture to warm to ambient temperature as the cold bath warms and stir overnight. Quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 849 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.30 (d, 1H), 7.19 (t, 1H), 7.05-7.01 (m, 3H), 6.98 (s, 1H), 6.93 (d, 2H), 5.96 (br. s, 2H), 4.26 (t, 1H), 3.02-2.94 (m, 3H), 2.86-2.76 (m, 3H), 2.44 (m, 1H), 2.33 (s, 3H), 1.84 (m, 1H).
Reaction SMILES: [CH:1](Cl)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:18]>C(#N)C.C(N(CC)CC)C>[CH:1]([N:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ncn(C(c2ccccc2)c2ccccc2)c1C(=O)OC
Temperature: 80 °C

Procedure:
20.3 g of benzhydryl chloride were added dropwise to a suspension of 18.4 g (0.1 mol) of 4,5-dimethoxycarbonyl-imidazole in 60 cc of acetonitrile and 14 cc of triethylamine and the reaction mixture was heated for 8 hours at 80° C. The solvent was then removed under reduced pressure and triethylammonium chloride was separated by washing with water. 30 g (85% of the theory) of 1-benzhydryl-4,5-dimethoxycarbonyl-imidazole, m.p. 93° C., were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.CC1C=NC=C(C2C=CC=CC=2)C=1.[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]3[CH:4]=[N:5][CH:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:8]=3)[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cncc(-c2ccccc2)c1
Agent: Cc1cncc(-c2ccccc2)c1
Solvent: CC#N
Product: c1ccc(-c2cncc(CN3CCN(c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.04 g of 3-chloromethyl-5-phenylpyridine (“A”) [obtainable for example by radical chlorination of 3-methyl-5-phenylpyridine] and 1.62 g of 1-phenylpiperazine are dissolved in 200 ml of acetonitrile and the mixture is stirred for six hours at room temperature. After customary work-up, 1-phenyl-4-[(5-phenyl-3-pyridyl)methyl]piperazine, m.p. 83-85°, is obtained.
Reaction SMILES: [F:1][CH2:2][C:3]([O-:5])=O.[Na+].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[NH2:24][CH2:25][C:26]([C:28]12[CH2:35][N:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2)=O>CN(C)C=O>[F:1][CH2:2][C:3]1[O:5][C:26]([C:28]23[CH2:35][N:32]([CH2:33][CH2:34]2)[CH2:31][CH2:30][CH2:29]3)=[CH:25][N:24]=1
Reactant: NCC(=O)C12CCCN(CC1)C2
Reactant: O=C([O-])CF
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: FCc1ncc(C23CCCN(CC2)C3)o1
Temperature: -15 °C
Reaction time: 0.04 h
Yield: 17.6 %

Procedure:
Sodium monofluoroacetate (110mg, 1.1 mmole) was dissolved in dry, distilled N,N-dimethylformamide (20ml), the solution cooled to -15° C., and N-methylmorpholine (0.114ml, 1.0 mmole) added, followed by isobutylchloroformate (0.176ml, 1.1 mmole). The resulting white suspension was stirred for 2-3 minutes. 5-(2-Aminoacetyl)-1-azabicyclo[3.2.1]octane dihydrochloride salt (D24A) (250mg, 1.0 mmol) was suspended in dry N,N-dimethylformamide (20ml) and N-methylmorpholine (0.228ml, 2.0 mmol) added. The resulting suspension was added immediately to the reaction mixture, the suspension stirred for 15-30 min and then allowed to warm to room temperature and stirred for 90 min. The reaction mixture was evaporated to dryness under reduced pressure and polyphosphoric acid (20g) added. The mixture was heated with stirring at 160° C. for 30 minutes and the warm syrup was then poured carefully onto a mixture of solid potassium carbonate and ice. The resulting aqueous solution was saturated with solid potassium carbonate and extracted with ethyl acetate (3×250ml) and chloroform (2×250ml). The organic extracts were dried (Na2SO4), filtered, combined and evaporated to dryness under reduced pressure. The resulting brown oil which was purified by column chromatography (basic alumina eluting with diethyl ether) to yield a pale yellow oil (37mg, 18%), which was converted into the hydrochloride salt m.p. 138°-141° C. (ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Br)ccc1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 5-bromo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 68.7% yield as a yellow crystalline solid, m.p. 118.7° C. (Rf=0.65 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:7]2.Cl.C(=O)(O)[O-:28].[Na+]>O1CCCC1>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:28])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
8-chloro-1,5-naphtpyridin-3-amine. A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C8H6ClN3=179.6.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3)ncn2-c2cccc(Br)c2C1=O

Procedure:
4.18 g (10 mmol) of 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 2 hours with 1.12 g (11 mmol) of phenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-bromo-4,5-dihydro-5-methyl-3-(phenylethynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-209°.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[S:16])[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)C>[OH-].[Na+].O>[CH3:21][S:16][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]=1
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of 3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (13.0 g, 54.6 mmol) in 2 M of sodium hydroxide in water (250 mL) was added dimethyl sulfate (6.2 mL, 66 mmol), and the reaction mixture was stirred at room temperature for 1 hour, then neutralized with acetic acid. The precipitate was collected by filtration and recrystallized from ethyl acetate-MeOH (1:1) to give the desired product (5.50 g, 40%). LCMS calculated for C11H17N4OS (M+H): 253.1. Found: 253.1.
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:44][O:45][CH2:46][C:47]([O:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10])=[O:48]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 105, 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine are reacted with 50 μl (0.495 mmol) of methoxyacetic acid chloride and 2 mg (0.017 mmol) of DMAP. To complete the reaction a further 0.5 equivalents of methoxyacetic acid chloride and a few granules of DMAP are added and the mixture is stirred. Extraction and digestion from DIPE/hexane in an ultrasound bath yields the pure title compound: TLC Rf (O)=0.48; tRet (V)=15.6 min; FAB-MS (M+H)+ =678.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[F:27][C:28]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:29]=1[O:30][CH2:31][CH2:32][CH2:33]OS(C)(=O)=O.O>C1COCC1>[F:27][C:28]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCCOc3cc(F)c(F)cc3F)c2=O)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (0.83 g, 3.0 mmol; from Example 48, Step 1) and t-BuOK (497 mg, 4.4 mmol) in THF (5 mL) was stirred for 10 min, and then added to methanesulfonic acid 3-(2,4,5-trifluoro-phenoxy)-propyl ester (0.80 g, 3.0 mmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 20% conversion. After 6 days, the reaction was worked up: water was added, THF was evaporated and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.33 g of the crude product as a yellow oil. HPLC analysis showed a 1/1 ratio between the title product and the isomeric O-alkylated product. Purification by chromatography on silica gel using EtOAc/hexane (1/3 to 1/1.7) as eluent gave 427 mg (30%) of the title product as a colorless oil. HPLC purity: 96%. MS m/z 469 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]([OH:9])[C:5](OC)=[O:6].[NH3:12].CO>>[F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]([OH:9])[C:5]([NH2:12])=[O:6]
Reactant: COC(=O)C(O)CC(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)C(O)CC(F)(F)F

Procedure:
A solution of 12-3 (200 mg, 1.16 mmol) in 7N NH3/MeOH (10 mL) was heated at 70° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and filtered to remove insolubles. The filtrate was concentrated to dryness to afford Intermediate 12. 1H NMR (500 MHz, DMSO-d6) δ 7.40 (br s, 1H), 7.34 (br s, 1H), 5.93 (m, 1H), 4.10 (m, 1H), 2.64-2.65 (m, 1H), 2.40-2.41 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 69.5 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)ethanol (0.134 g, 0.89 mmol) and 4M HCl in dioxane (0.222 mL, 0.89 mmol) in EtOH was heated for 2.5 h at 85° C. After this time, the mixture was neutralized with NaHCO3 at 0° C. and purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.145 g, 70%) as a yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 9.53 (s, 1H), 8.33-8.28 (m, 2H), 7.62-7.55 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 4.62 (t, J=5.2 Hz, 1H), 3.63-3.59 (m, 2H), 2.72-2.64 (m, 4H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 354 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:3]1=[O:17].[O:18]=[C:19]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]2)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][C:35]([N:32]3[CH2:33][CH2:34][CH:29]([N:28]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:18])[CH2:30][CH2:31]3)=[O:36])[C:3]2=[O:17])=[CH:15][CH:14]=1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@@H]1CCCCN(Cc2ccc(O)cc2)C1=O
Product: O=C(N[C@@H]1CCCCN(Cc2ccc(O)cc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3R)-3-amino-1-(4-hydroxybenzyl)azepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 16. MS 492.2591 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(CNc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-3-nitrobenzotrifluoride (5.05 g, 22.4 mmol), 4-(dimethylamino)-benzylamine dihydrochloride (5.0 g, 22.4 mmol), potassium carbonate (9.29 g, 76.2 mmol) and dimethylformamide (60 ml) was stirred at room temperature for 3 days. Water (60 ml) was added and the mixture was stirred for 0.5 h followed by filtration. The crystalline product was triturated with petroleum ether. Yield 6.08 g, 80%. M.p. 158-160° C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[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.Cl.N1C=CN=C1.[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].O>C(OCC)C>[Si:36]([O:25][C:3]1[CH:2]=[CH:1][C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C:5]=2[C:4]=1[O:19][C@H:18]4[C:20](=[O:21])[CH2:22][CH2:23][C@@:9]35[OH:24])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
3.49 g of naltrexone hydrochloride was suspended in 10.5 ml of N,N-dimethylfonnamde. After adding 3.46 g of imidazole, 3.48 g of tert-butyldimethylchlorosilane was added followed by stirring for 35 minutes at room temperature. 30 ml of water and 50 ml of diethyl ether were added to the reaction system followed by separation. The aqueous layer was extracted twice with 30 ml of diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was recrystallized from ethanol to obtain 3.2 g of the target compound (yield: 76%).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([I:20])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:21])[C@@H:8]1[OH:22])([OH:4])([OH:3])=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.N1C=CC=CC=1SSC1C=CC=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CN(C=O)C>[CH2:24]1[N:23]([P:1]([O:5][CH2:6][C@H:7]2[O:11][C@@H:10]([N:12]3[C:13](=[O:14])[NH:15][C:16](=[O:17])[C:18]([I:20])=[CH:19]3)[C@H:9]([OH:21])[C@@H:8]2[OH:22])([OH:3])=[O:4])[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)cc1I
Reactant: C1COCCN1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)N3CCOCC3)[C@@H](O)[C@H]2O)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.9 %

Procedure:
5-Iodouridine-5′-monophosphate 1 (292 mg, 0.65 mmol) was dissolved in dry DMSO, co-evaporated (3×) with dry DMF, and finally dissolved in 0.5 mL of dry DMSO. Morpholine (400 μL, 4.6 mmol) was added and the reaction mixture was stirred at room temperature for 5 min. Dipyridyl disulfide (500 mg, 2.3 mmol) and triphenylphosphine (600 mg, 2.3 mmol) were added in 5 min intervals, and the reaction mixture was stirred for another 60 minutes at room temperature. Upon quenching of the reaction with 0.1 M NaI in acetone a precipitate formed. The supernatant was removed, and the precipitate was washed repeatedly with cold acetone, to give 354 mg (99% yield) of 5-Iodouridine-5′-phosphoromorpholidate as a white powder. This material was used in the next step without further purification. δH (400 MHz, D2O) 3.04-3.16 (4H, m, H-Morpholine), 3.65-3.73 (4H, m, H-Morpholine), 4.00-4.15 (2H, m, H-5′), 4.24-4.26 (1H, m, H-4′), 4.27-4.32 (1H, m, H-3′), 4.36 (1H, t, J=5.4 Hz, H-2′), 5.94 (1H, d, J=5.8 Hz, H-1′), 8.17 (1H, s, H-6). δC (75.5 MHz, D2O) 64.3 (morpholine), 63.3 (d, J=5.4 Hz, C-5′), 66.3 (morpholine), 67.8 (C-5), 68.6 (C-3′), 73.2 (C-2′), 83.0 (d, J=8.4 Hz, C-4′), 88.2 (C-1′), 145.0 (C-6), 153.3 (C-2), 161.9 (C-4); OP (121.5 MHz, D2O) 11.0 ppm. m/z (ESI) 519.9968 [M+H]+, C13H19IN3O9P requires 519.9976.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([O:21][CH2:22][CH3:23])[CH:15]=[C:14]2[C:9]=1[CH2:10][O:11][C:12]2=[O:13])[CH3:6].[N+:24]([O-])([OH:26])=[O:25]>O>[CH2:5]([O:7][C:8]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([O:21][CH2:22][CH3:23])[C:15]([N+:24]([O-:26])=[O:25])=[C:14]2[C:9]=1[CH2:10][O:11][C:12]2=[O:13])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc2c(c(OCC)c1OCC)COC2=O
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Reaction time: 8 h
Yield: 35 %

Procedure:
Glacial acetic acid (14 ml) was added to 5.32 g (0.02 mole) of 4,5,6-triethoxyphthalide. Into the reaction mixture on a water bath at 30-35° C., 14 ml of fuming nitric acid, d=1.52, was gradually added dropwise over a time period of 9 hours. After completion of the addition, the reaction mixture was allowed to stand overnight at room temperature and thereafter 80 ml of water was added to deposit crystals. The crystals were filtered out, washed thoroughly with water and dried. There was obtained 2.20 g of 4,5,6-triethoxy-7-nitrophthalide having a melting point of 82.5-84.5° C. with a yield of 35%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and 4-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzamide as a white powder, m.p. 90.5-91.5° C. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (t, J=5.7 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.21 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.61 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.25 (m,2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 451.2008 (451.2008 calcd for C27H25N5O2).