Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][S:2]([O:22][CH2:21][C:13]1[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1oc2ccccc2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (160 μL, 2.05 mmol) was added dropwise to a solution of (3-phenylbenzofuran-2-yl)methanol (367 mg, 1.64 mmol) and DIPEA (343 μL, 1.97 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2 h stirring at RT, additional amounts of methanesulfonyl chloride (80 μL, 1.03 mmol) and DIPEA (172 μL, 0.99 mmol) were added and stirring was continued for 1.5 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzofuran-2-yl)methyl methanesulfonate as an oil (443 mg, 89%). 1H NMR (DMSO, 400 MHz): δ 7.71-7.64 (2H, m), 7.62-7.56 (4H, m), 7.52-7.41 (2H, m), 7.37-7.32 (1H, m), 4.98 (2H, s), 3.89 (3H, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](I)=[N:9]2)=[N:6][CH:7]=1.[CH3:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:22]3[S:21][C:20]([CH3:19])=[N:24][CH:23]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1nccs1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cn2)nc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cn2)nc1-c1cnc(C)s1
Temperature: 140 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 1-(5-fluoropyridin-2-yl)-3-iodo-1H-pyrazole-4-carboxylate (0.40 g, 1.11 mmol) in DMF (3.7 mL) were added 2-methyl-1,3-thiazole (0.17 g, 1.66 mmol), palladium(II) acetate (25.0 mg, 0.11 mmol), triphenylphosphine (58.0 mg, 0.22 mmol) and cesium carbonate (0.72 g, 2.22 mmol). The mixture was heated 140° C. in a seal vial. After 2 h, water and saturated aqueous NaHCO3 were added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes 50% hexanes/ethyl acetate) gave the title compound (0.24 g). MS 333.1 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1Br.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCOCC1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(C)n1nc(-c2nc(-c3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (220 mg) in water (1.6 ml) was added to a suspension of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg), phenylboronic acid (158 mg) and tetrakis(triphenylphosphine)palladium (18 mg) in dioxane (6 ml) and the mixture was stirred at 100-105° C. for 2 hours. After addition of water (6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-3,6-diphenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-tert-Butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL acetone. 552 mg K2CO3 (4 eq) was added, followed by addition of Mel (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously at 60° C. overnight. After removal of the acetone, the residue was shaken with DCM. Filtration and evaporation of the solution yielded 221 mg product which was used as such.
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[NH:1]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]2[O:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OCCCO2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Reaction time: 3 h
Yield: 94.9 %

Procedure:
13.5 g of 7-acetamino-3,4-dihydro-2H-1,5-benzodioxepine were placed in 50 ml of glacial acetic acid and nitrated at 15°-20° C. with 7 ml of nitric acid in 20 ml of glacial acetic acid by dropwise addition, the crystals passing into solution only after the addition of a quarter of the nitric acid. The product separated out, but was stirred for an additional 3 hours, then removed under suction and washed with water and methanol. 15.6 g (94.9% of theory) of 7-acetamino-8-nitro-3,4-dihydro-2H-1,5-benzodioxepine of melting point 139°-140° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[Br:18]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Yield: 76.1 %

Procedure:
To a mixture of compound from step A (2 g, 8.61 mmol) and N-bromosuccinamide (1.84 g, 10.33 mmol) in carbon tetrachloride (50 ml) was added benzoyl peroxide (209 mg, 0.86 mmol) and the resulting mixture heated at reflux for 4 h. The reaction mixture cooled and filtered through celite, and filtrate evaporated. The residue purified by MPLC (Biotage Horizon: FLASH 40+s) eluent: 100% Hexanes (190 ml), gradient rising from 100% hexanes to 10% EtOAc in Hexanes (1000 ml), then 10% EtOAc in Hexanes (250 ml) to afford the title compound 2.04 g (76%). 1H NMR (CDCl3): 1.75 (s, 9H), 4.82 (s, 2H), 7.39 (m, 1H), 7.58 (m, 1H), 7.87 (d, J 8.0 Hz, 1H), 8.15 (d, J 8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][C@H:30]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[C:40]([CH:43]=O)[CH:39]=[CH:38]2)[CH3:31].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:43]([C:40]3[CH:39]=[CH:38][C:37]4[C:42](=[C:33]([O:32][C@H:30]([CH3:31])[CH2:29][O:28][CH3:27])[CH:34]=[CH:35][CH:36]=4)[N:41]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COC[C@@H](C)Oc1cccc2ccc(C=O)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC[C@@H](C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.33 g, 0.87 mmol) and (R)-8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.21 g, 0.87 mmol) in ethanol (4.3 mL, 0.87 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.3 mL) and iodosobenzene diacetate (0.31 g, 0.95 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (25-100% acetonitrile/water) to give the title compound (0.38 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:36]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:36][O:24][C:23]([C:18]2([C:20]([O:22][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OCC1CCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CCCCC1)(C(=O)OCC1CCCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclohexylmethanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.80-1.80 (m, 22H), 1.33 (bs, 3H), 2.80 (m, 1H), 3.18 (m, 2H), 3.48 (m, 2H), 4.10 (m, 4H), 5.50 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 614 (MH+); [α]D25 -22° (c, 1.0, CHCl3). Anal. Calcd. for C34H44ClNO7 ·HCl: C, 62.77; H, 6.82; N, 2.15; Cl, 10.90. Found: C, 61.83; H, 7.27; N, 2.07; Cl, 10.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Br-:13].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.CC(=O)OCC>CO.C1COCC1>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:12]
Reactant: COc1cc(Br)cc(C(C)=O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 123 %

Procedure:
1-(3-Bromo-5-methoxyphenyl)ethanone (O2.032, 1.45 g) was dissolved in methanol/THF (40 ml/40 ml) and admixed while stirring with phenyltrimethylammonium tribromide (2.38 g). After stirring at RT for 24 h, water and EA were added. The EA phase was removed, dried and concentrated. The residue was dissolved in acetonitrile (50 ml), and 2 N sulfuric acid (15 ml) was added to the solution. After standing at RT for 1 h, the mixture was admixed with water and extracted twice with EA. The EA phase was washed with saturated sodium hydrogencarbonate solution, dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 30 min. 1.39 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1-n1ccnc1
Yield: 96.4 %

Procedure:
4-Chloro-3-nitropyridine (2.00 g, 12.6 mmol) and imidazole (2.25 g, 33.0 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto, followed by reaction at 90° to 100° C. for 1.5 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: dichloromethane:methanol=10:1 (v/v)] to obtain 2.31 g of a yellow liquid (yield: 96.4%).
Reaction SMILES: C(O)(C)(C)C.[SH2:6].[N+:7]([C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[SH-].[K+:20]>CCOCC>[N+:7]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[S:6])[S-:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[K+:20]
Reactant: S
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Agent: [K+]
Agent: [SH-]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(NC(=S)[S-])c1
Reaction time: 2 h

Procedure:
A mixture of 75.0 grams of potassium t-butylate in 500 ml. of t-butyl alcohol is saturated with hydrogen sulfide. With the temperature kept below 35°C. by cooling, a mixture of 120.0 grams of m-nitrophenyl isothiocyanate in 500 ml. of ether is added to the potassium hydrosulfide solution in three portions. After the mixture is stirred an additional two hours, the solids are collected by filtration, washed with ether, and dried under vacuum to give 162 grams of potassium m-nitrophenyldithiocarbamate. This salt is added portionwise over about 15 minutes to a stirred ice-cooled mixture of 174 grams of methylene bromide and 65 grams of triethylamine in 600 ml. of dimethylformamide with the reaction temperature at 25°C. to 30°C. After another five hours of stirring at room temperature, the mixture is poured into 3.5 liters of ice-water precipitating a light yellow solid. The solids, after drying, are taken up in benzene (ca. 2 liters), filtered free of some insoluble material, and the benzene mixture is saturated with dry hydrogen chloride. The precipitated solids are collected by filtration, washed with benzene, and then stirred vigorously with a water-benzene mixture at 60°C. to 70°C. The benzene layer is separated, washed with water and sodium bicarbonate solution, dried, and concentrated in vacuo to give 102 grams of crude product. The solids are dissolved in 800 ml. of ethanol. The mixture is filtered and diluted with 1200 ml. of ether. Then the mixture is cooled to -35°C. The resulting light yellow solids are collected and vacuum dried to give 84.0 grams of product, melting point 96.0°C. to 97.0°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N+:23]([C:22]1[C:17]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-cyanophenol (187 mg, 1.06 mmol) was dissolved in DMF (1 mL) and cesium carbonate (360 mg, 1.1 mmol) was added followed by a solution of 2-chloro-3-nitropyridine (158 mg, 1.0 mmol) in DMF (1 mL). The reaction mixture was heated with shaking at 80° C. for 18 h. The mixture was concentrated. The residue was dissolved in ethyl acetate (4 mL) and washed with water (0.6 mL), saturated NaHCO3 (0.5 mL) and water (2×0.5 mL). The organic phase was concentrated and the resulted mixture containing mainly 106a was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5](=[O:8])[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:7]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(Cc2ccc(F)cc2)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To an 8 mL screw-cap vial was added N,N-dimethylformamide (DMF; 1.5 mL), N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), anhydrous potassium carbonate (K2CO3; 138 mg, 1.0 mmol), and 4-fluorobenzyl bromide (113 mg, 0.60 mmol). The mixture was shaken and heated to 70° C. for 2 h and then at room temperature for an additional 16 h. The crude reaction mixture was filtered and placed directly onto a reverse phase chromatography column. After elution, the title compound was isolated as a white solid (30 mg, 20%): mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.49-7.43 (m, 2H), 7.10-7.01 (m, 2H), 5.33 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H); ESIMS m/z 293 ([M+H]+).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)c2ccccc2)c(O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen was reacted with 16 g. of sodium methoxide and then with 14 g. of benzoyl chloride. The product was isolated as the free base, 3-hydroxy-4-(benzoyloxy)phenyl tert-butylaminomethyl ketone [20 g; m.p. 150°-165° C. (dec.)(uncorr.)], which was converted to 13 g. of its methanesulfonate, m.p. 245° C. (dec.)(uncorr.). By catalytically hydrogenating this salt, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[F:8][C:9]1[C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:13][CH:12]=[CH:11][N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)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>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:14]1[C:9]([F:8])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1ccsc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1ncccc1-c1sccc1Br
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dibromothiophene (2.86 g), 2-fluoro-3-tributylstannylpyridine (3.93 g), Pd(Ph3P)2Cl2 (0.153 g) in N-methylpyrrolidinone (25 mL) was heated at 75° C. under argon for 3.5 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (1.07 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([C@@H:15]([CH3:25])[CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:13]([CH2:26]Cl)=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.O.ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:25])[CH2:16][O:17][CH2:26][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3cc(Br)ccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1COCc2nc3cnc4cc(Br)ccc4c3n21
Temperature: 1 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
A 2-L, three-necked, Morton flask, equipped with mechanical stirrer, was charged with 7-bromo-1-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (38.0 g, 81.0 mmol) and 1,2-dichloroethane (900 mL) and the mixture was cooled to 1° C. A 1.0 M solution of tetrabutylammonium fluoride in THF (90 mL, 90 mmol) was slowly added over 1.5 hours. The reaction temperature was maintained at 1-2° C. during addition. The reaction was allowed to slowly warm to ambient temperature and stirring was continued for 2 days. The reaction was treated with saturated aqueous K2CO3 solution (500 mL) and H2O (400 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (3×100 mL). The organic layers were combined and concentrated under reduced pressure to give a tan solid. Chromatography (SiO2, 0-6% methanol/CH2Cl2) gave 12.5 g of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as an off-white solid which was used without further purification. A small sample was crystallized from acetonitrile to give white crystals, mp 207-209° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(=O)([O-])O.[Na+].CN(C)C(=O)C>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:17][CH2:16][C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: NCc1ccco1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccccc1NCc1ccco1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 15.7 parts of 1-chloro-2-nitrobenzene, 9.7 parts of 2-furanmethanamine, 8.4 parts of sodium hydrogen carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at about 120° C. The reaction mixture was cooled, water was added and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was triturated in petroleumether. The product was filtered off and dried, yielding 15 parts of N-(2-nitrophenyl)-2-furanmethanamine; mp. 85.6° C. (intermediate 1).