Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][N:15]([C:41]([C:40]4[CH:39]=[C:38]([CH:46]=[CH:45][CH:44]=4)[CH2:37][NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:42])[CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccnc3c2CNCCO3)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N2CCOc3nccc(-c4ccc(F)cc4)c3C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.20 g) obtained in Reference Example 13C, 1-hydroxy-1H-benzotriazole (0.15 g), triethylamine (0.083 g) and 3-(tert-butoxycarbonylaminomethyl)benzoic acid (0.205 g) in acetonitrile (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.314 g), and the mixture was stirred at room temperature for 20 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (0.35 g) as a colorless amorphous powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 12 h
Yield: 83.6 %

Procedure:
A mixture of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (97.6 g, 0.339 mol), 2-[(diethylamino)methyl]piperidine (64.0 g, 0.376 mol), sodium carbonate (36.0 g, 0.34 mol) and n-propanol (1.7 liters) is refluxed for 5 hours. The reaction mixture is filtered while hot then left to stand for 12 hours at ambient temperature, after which the desired product is found to have precipitated in crystalline form. The substance is suction filtered, washed 3 times, each time with n-propanol (100 ml), and dried in a vacuum drying chamber. Colorless crystals (119.5 g) are obtained, Mp. 226°-229° C.
Reaction SMILES: [CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[Cl-].[Cl:12]C=[N+](C)C>ClCCl>[CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3]([Cl:12])=[O:4]
Reactant: C[N+](C)=CCl
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reaction time: 1.5 h

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH2:10][OH:11]>C(OCC)(=O)C>[OH:11][CH2:10][C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)CO
Solvent: CCOC(C)=O
Product: OCc1nc2ccccc2s1
Yield: 69.5 %

Procedure:
60 g of 2-aminothiophenol and 36.6 g of glycolic acid were heated at 130° C. in a sealed tube for 12 h. The reaction product was dissolved in ethyl acetate and dried over sodium sulfate and the solvent was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 55 g of the titled compound in the form of white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:28])([CH3:27])[CH2:12][C@H:13]1[CH2:17][O:16]C(C)(C)[N:14]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(C(OCC)=O)C1)=O)CCC>CO>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:28])([CH3:27])[CH2:12][C@H:13]([NH:14][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OCC)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(CCOCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
The title compound is prepared starting from 75.2 g of 4(S)-(4-benzyloxy-2,2-dimethylbutyl)-3-tert-butoxycarbonyl-2,2-dimethyl-1,3-oxazolidine and 2.0 g of p-toluenesulfonic acid hydrate in 500 ml of methanol analogously to Example 20a): Rf (A)=0.31; FAB-MS: (M+H)+ =352; anal. calc. for C20H33NO4 : C68.34%, H9.46%, N3.99%; found C68.14%, H9.37%, N3.98%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4](Cl)[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.[Al]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 55 %

Procedure:
A microwave vessel was charged with a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.165 g, 0.88 mmol) in ethanol (3 mL). p-Toluenesulfonic acid (0.167 g, 0.88 mmol) and ethyl 2-(4-aminophenyl)acetate (0.157 g, 0.88 mmol) were added and the vessel was sealed with an aluminum cap. The mixture was heated to 120° C. for 2 d, cooled, diluted with satd. aq. sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.160 g, 55%) as an orange oil. MW=330.81. 1H NMR (CDCl3, 500 MHz) δ 7.33-7.28 (m, 2H) 7.16-7.12 (m, 2H), 6.74 (s, 1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 331 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][C:34]=3[O:36][CH3:37])=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(-c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, the product of Step 3 (25 g), 2,4-dimethoxyphenylboronic acid (11.1 g) and sodium carbonate (14.2 g) were stirred in 1,2-dimethoxyethane (125 mL) and deionized water (40 mL). A nitrogen purge line was inserted directly into the reaction mixture for 10 minutes and then removed. Tetrakis(triphenylphosphine)palladium(0) (1.4 g) was added to the reaction mixture. It was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into a beaker containing deionized water (1 L) and ice. Concentrated hydrochloric acid was added while stirring vigorously until the pH reached 3. The mixture was transferred to a separatory funnel and extracted with chloroform 3 times (400 mL each time). The organic layers were recovered, combined and then placed directly onto a silica gel column (600 g) eluting with a mixture of 30% ethyl acetate/70% hexanes. Fractions containing product were combined and concentrated by rotary evaporation. The resulting residue was slurried in a minimal amount of a solution of 10% ethyl acetate/90% hexanes. A solid precipitate was collected by vacuum filtration. 25.4 grams of methyl 4-acetoxy-1-(2′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-7-methoxy-2-naphthoate was isolated.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(O[C:4](C)(C)[CH3:5])=O.[N+:16]([CH2:19][C@@H:20]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:38]=1)[CH2:21][C:22]([N:24]1[C@H:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]1=[O:36])=[O:23])([O-])=[O:17].C(Br)=C.C1COCC1>CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:17]1[CH:5]=[CH:4][C:19]([C@@H:20]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:38]=2)[CH2:21][C:22]([N:24]2[C@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][O:26][C:25]2=[O:36])=[O:23])=[N:16]1
Reactant: O=C(C[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=CBr
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
At room temperature, di-t-butyl dicarbonate (0.502 g, 2.30 mmol) was added to a solution of (R)-4-benzyl-3-((R)-3-(3-(benzyloxy)phenyl)-4-nitrobutanoyl)oxazolidin-2-one (94.1B) (0.727 g, 1.53 mmol), vinyl bromide, (1.0 M solution in THF (16.9 mL, 16.9 mmol), N,N-dimethylpyridin-4-amine (DMAP) (0.0187 g, 0.153 mmol) and TEA (0.256 mL, 1.84 mmol). The mixture was stirred at room temperature for 24 hours. The reaction was then diluted with EtOAc (200 mL) and washed with sodium bicarbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:2 EtOAc/hexane) and gave 558 mg of 94.1C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:51]=[CH:50][C:6]([CH2:7][N:8]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:9]2[C:13]3[CH:14]=[N:15][C:16]([NH:18]C(=O)[O-])=[CH:17][C:12]=3[N:11]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C:9]2[C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:10]=2)=[CH:50][CH:51]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(NC(=O)[O-])ncc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3-(bis(4-methoxybenzyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (0.4 g, 0.55 mmol) in THF (8 mL) was added TBAF (1.0 M solution in THF, 10 mL) and the contents were heated to reflux. After 12 h, the reaction was cooled back to ambient temperature, quenched with 1N HCl (5 mL) and stirred at ambient temperature for 1 h. The reaction mixture was further diluted with EtOAc (25 mL) and the organic layer was separated. The organic layer was washed with brine (1×20 mL), dried over anhydrous Na2SO4 and the solvents were removed under reduced pressure. The residue thus obtained was purified by a filter column to afford the title compound. MS ES calc'd. for C41F137N5O2 [M+H]+ 632. Found 632.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[C:12]([CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:11]=1>C(O)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:18][CH:19]=1)[C:14](=[O:15])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20]2
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CCCCC(=O)Cc1cc(Br)ccc1C(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
4-Fluoroaniline (98 mg, 0.884 mmol, 1.0 equiv.) was added to a stirred mixture of methyl 4-bromo-2-(7-methoxy-2,7-dioxoheptyl)benzoate (328 mg, 0.884 mmol) in acetic acid (1 mL) and the mixture was stirred at 100° C. for 90 min. After cooling to room temperature, the excess solvent was concentrated, diluted with water and extracted with EtOAc (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-10% EtOAc/hexanes to give 193 mg of methyl 5-(6-bromo-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[N:9]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCCO4)cc1C
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccnc3)c3cc4c(cc3c2=O)OCCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 58 mg (0.17 mmol) of 8-(3,4-dimethyl-benzoyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one, 18 mg of 60% sodium hydride, 57 mg of 3-bromomethylpyridine hydrobromide and 1.2 mL of N,N-dimethylformamide. Yield: 55 mg of a white solid: LC-MSD, m/z for C26H22N2O4 [M+H]+=427.5; HPLC retention time: 1.6 min.
Reaction SMILES: Cl[CH2:2][P:3](=[O:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([NH:14][CH2:2][P:3](=[O:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: CP(C)(=O)CCl
Solvent: CCO
Product: CP(C)(=O)CNCc1ccccc1
Yield: 63 %

Procedure:
A solution of 316.3 g of chloromethyl-dimethylphosphine oxide, 547 ml of benzylamine and 500 ml of ethanol is refluxed for 18 hours. After cooling to 20° to 25° C., the turbid suspension is filtered; the clear filtrate is then concentrated by evaporation, and to the residue are added 500 ml of 10% sodium chloride solution. The aqueous solution is extracted 4 times with 500 ml of methylene chloride each time; and the combined organic phases are subsequently dried over sodium sulfate and concentrated by evaporation. Vacuum distillation of the oily crude product yields 311.0 g (63% of theory) of N-benzyl-P,P-dimethyl-aminomethylphosphine oxide in the form of yellowish oil, b.p. 150° C./0.2 mb.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[N:17]([CH3:20])[C:12]2[N:13]=[CH:14][N:15]([CH3:16])[C:11]=2[C:9]1=[O:10])=[O:3].C(Cl)Cl.[BH4-].[Na+]>CO>[OH:3][CH:2]([CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9](=[O:10])[C:11]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:17]([CH3:20])[C:18]1=[O:19]
Reactant: CC(=O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Pentoxifylline (1.0 g, 3.59 mmol) was dissolved in methanol (20 mL) and DCM (3 mL) then cooled to 0° C. To the reaction was added sodium borohydride (0.41 g, 10.8 mmol) portionwise over 30 min. The reaction was stirred in the cold for 2 h; then it was evaporated to dryness under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(5-hydroxyhexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (0.72 g, 71% yield) as a white solid. LCMS retention time=1.849 min and 98% purity, LCMS MH+ 281. 1H NMR (DMSO-d6) δ 8.00 (s, 1H), 4.31 (d, 1H, J=4 Hz), 3.88 (s, 3H), 3.84 (t, 2H, J=8 Hz), 3.51-3.59 (m, 1H), 1.45-1.56 (m, 2H), 1.25-1.37 (m, 4H), 1.02 ( d, 3H, J=4 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.Cl.[CH2:16]([O:19][NH2:20])[CH:17]=[CH2:18].C(N(CC)CC)C>O1CCOCC1>[CH2:16]([O:19][NH:20][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1)[CH:17]=[CH2:18]
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: C=CCON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (3.75 g, 16 mmol), O-allylhydroxylamine hydrochloride (1.8 g, 16.4 mmol) and triethylamine (9.1 ml, 66 mmol) in dioxan (80 ml) was stirred at 100° C. for 6 hours. The cooled reaction mixture was filtered and evaporated to dryness under reduced pressure. The residue was on silica gel (eluted with chloroform chromatographed methanol, 10:1) and the product recrystallised from chloroform-methanol affording the title compound (2.1 g, 48%), m.p. 170°-181° C. IR: υmax (KBr) 3240, 1705, 1650, 1590, 1570, 1495, 1465, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 4.37 (2H, d, J=6 Hz, CH2ON), 5.28 (2H, m, CH=CH2), 6.00 (1H, m, CH=CH2), 8.17 (1H, s, CHO), 9.30 (1H, s, CHO), 9.45 (1H, br.s, NH), 10.87 (2H, br.s, 2×NH). Found: C, 39.64; H, 3.49; N, 25.34%, M+ 271.0469. C9H10ClN5O3 requires C, 39.79; H, 3.71; N, 25.78%, M+ 271.0469.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=O)=[CH:7][C:6]=1[O:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(C1C=CC(OCC(O)=O)=CC=1OC)(C)(C)C.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([NH:64][S:65]([CH3:68])(=[O:67])=[O:66])=[C:60]([F:69])[CH:59]=1>C(N(CC)CC)C.C(Cl)Cl.O1CCCC1>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([NH:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([NH:64][S:65]([CH3:68])(=[O:67])=[O:66])=[C:60]([F:69])[CH:59]=2)=[O:13])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OCC(=O)OC(C)(C)C)ccc1C(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: COc1cc(OCC(=O)O)ccc1C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
A mixture of tert butyl (4-tert-butyl-3-methoxyphenoxy)acetate (466 mg, 1.6 mmol), trifluoroacetic acid (2.0 ml), tetrahydrofuran (THF) (3.0 ml) and methylene dichloride (2.0 ml) was stirred for 1 hour at ambient temperature. After being concentrated under reduced pressure, the residue was used for further reaction without purification (460 mg). Then (4-tert-butyl-3-methoxyphenoxy)acetic acid (460 mg, crude), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (97 mg, 0.6 mmol), triethylamine (0.33 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (160 mg, 0.63 mmol) were treated in the same procedure described in Example 2(b) to give 8.1 mg (1.1% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=[C:34]([C:46](=[NH:49])[NH:47]O)[N:33]=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]1[N:37]=[C:32]([NH2:31])[N:33]=[C:34]([C:46]2[N:47]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:10]=3)[O:16][N:49]=2)[N:35]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Reactant: O=C(O)c1ccc(OCCOCC(F)(F)F)nc1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCCOCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
6-[2-(2,2,2-Trifluoroethoxy)ethoxy]pyridine-3-carboxylic acid (Intermediate 242, 0.133 g, 0.50 mmol) and 1,1′-carbonyldiimidazole (0.081 g, 0.50 mmol) were combined in pyridine (3 mL) and stirred at room temperature for 3 h. 4-Amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.100 g, 0.39 mmol) was added and the mixture stirred at room temperature for 4 h before being heated to 80 C for 16 h. Pyridine was removed under vacuum and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was dried over sodium sulfate and concentrated to yield an orange solid. This was purified by FCC, using a gradient of 30-70% EtOAc in heptane to afford the title compound as a white solid (0.116 g, 61%). Method A HPLC-MS: MH+ requires m/z=489 Found: m/z=489, Rt=4.58 min (100%). 1H NMR (500 MHZ, CDCl3) δ ppm 9.06 (1H, s), 8.41 (1H, d), 7.47 (2H, m), 7.34 (3H, m), 6.96 (1H, d), 5.34 (2H, br s), 4.64 (2H, t), 4.04 (2H, t), 3.97 (2H, q) and 3.65 (3H, s).