Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2cc(O)ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc2c(c1)OCCC2(C)C
Yield: 99.3 %

Procedure:
4,4-Dimethylchroman-7-ol (1.4 g, 8.0 mmol), potassium carbonate (3.3 g, 24.0 mmol) and ethyl bromoacetate (1.0 mL, 9.2 mmol) were treated in the same procedure described in Example 33(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 4/1) to furnish 2.1 g (98% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.BrC1C=CC(F)=C([N+]([O-])=O)C=1.F[C:25]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=1[C:27]#[N:28].ClCCl>C(O)C.C(OCC)C>[C:27]([C:26]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:28]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1NCCc1c[nH]c2ccccc12
Yield: 40 %

Procedure:
2×500 mg (2×1 equiv) of tryptamine were dissolved under an argon atmosphere in 2×2 ml of absolute ethanol in three different flasks of a Carousel parallel synthesizer. 4-bromo-1-fluoro-2-nitrobenzene (690 mg, 1 equiv) and 2-fluoro-5-nitrobenzonitrile (520 mg, 1 equiv) were added, respectively, in one of the two parallel flasks (A and B) and the obtained mixtures were allowed to react at room temperature under magnetic stirring. The course of the reactions was followed by TLC (dichloromethane as the eluent). Reactions A and B were completed after 8 and 2 hours, respectively. The two mixtures were then diluted with ca. 15 ml of diethyl ether and the resulting precipitates were collected by filtration and washed with additional Et2O. TLC analyses showed in all precipitates residual traces of starting materials, thus each reaction mixture was purified by column chromatography on silica gel (approx. 20 grams). A mixture of petroleum ether/dichloromethane (8:2) was used until the starting nitroaromatic derivatives were eluted; subsequently, the target products were eluted by using dichloromethane. N-(2-nitro-4-bromophenyl)-tryptamine was collected as a red solid in 55% yield and finally N-(2-cyano-4-nitrophenyl)-tryptamine was obtained as a yellow solid in 40% yield.
Reaction SMILES: C(O)(=O)C.O.[O:6]=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]([O:34]C1CCCCO1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]>O1CCCC1>[OH:34][CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])/[CH:24]=[CH:23]/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7](=[O:6])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To 1ml of a 3:1:1 solution of acetic acid, water, and tetrahydrofuran (THF) was added 20mg (0.041 mmol) of the titled product of Example 10 and the reaction mixture was allowed to stir 16 hr. After this time, some insoluble oil was still present and approximately 50μl of THF was added to the reaction mixture and it was stirred for an additional 2 hours. The volatile components were removed in vacuo and the residue was flash chromatographed. Elution with 1:1 diethylether-hexane produced 10mg of the desired product.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[C:18](OC(=O)C)(=O)[CH3:19].O>N1C=CC=CC=1>[CH3:18][C:19]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 4-(N-hydroxycarbamimidoyl)piperazine-1-carboxylate (771 mg, 3.16 mmol) in pyridine (8 mL) was added acetic anhydride (320 L, 3.42 mmol) and the reaction was heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 774 mg of a yellow solid. After purification by flash chromatography (silica, gradient of 0.5 to 3% methanol in dichloromethane) 509 mg of an off-white solid were obtained (1.897 mmol, 60%). MS (ESI) m/z=291.1 [M+Na]+.
Reaction SMILES: [N:1]1[C:2]([CH2:10][NH2:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]1[N:11]([CH2:10][C:2]2[N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[CH:3]=2)[C:14](=[O:13])[CH2:15][CH2:18][CH2:19]1
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1cn2ccccc2n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cn2ccccc2n1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available imidazo[1,2-a]pyridin-2-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.50 min.; [M+H]+: 366.12 g/mol.
Reaction SMILES: Cl.[CH2:2]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:29][CH2:28]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([N:29]1[CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][S:27][CH2:28]1)=[O:22])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)C1CSCN1
Reactant: CCCCCCCCCCC=CCCCNc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=CCCCNc1cccc(C(=O)N2CSCC2C(=O)OCC)c1

Procedure:
One-tenth mole of 3-(4-pentadecenylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O1CCCC1.O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (60 g, 472 mmol) in tetrahydrofuran/water (=1/1, 600 mL) was added sodium hydrogen carbonate (43.6 g, 519 mmol), and benzyl chloroformate (74.1 mL, 519 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 16 hr, 2N hydrochloric acid (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (82.5 g, 67%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (17.7 g, 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.O.[NH2:46][NH2:47]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([NH:46][NH2:47])=[O:20])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NN
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1cc(C(=O)NN)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-(2-fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (5.62 g, 14.5 mmol) in DMF (50 mL) was added pyridine (3.5 mL, 43.4 mmol) then followed by dropwise addition of pentafluorophenyl trifluoroacetate (4.5 mL, 43.4 mmol). The mixture was stirred at room temperature for 24 hours. To this mixture was added hydrazine monohydrate (2.8 mL, 58 mmol). The reaction mixture was stirred at room temperature for another 24 hours. The precipitated white solid was collected by filtration and washed with water (5 mL) and hexanes. After drying, the 4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid hydrazide was obtained as a white solid (6.55 g, 81%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.90 (s, 1H), 9.63 (s, 1H), 8.15 (s, 1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.26 (t, 1H), 5.58 (s, 1H), 4.42 (br s, 1H), 2.50 (t, 3H). Anal. Calcd for C15H14FIN2O3: C, 43.3; H, 3.4; N, 6.7. Found: C, 43.7; H, 3.1; N, 7.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:18])[C:5]=1[O:19][CH3:20].[CH:21]1([N:24]=[C:25]=[S:26])[CH2:23][CH2:22]1.[CH3:27]I>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:17])=[C:11]([CH2:27][S:26][CH:25]=[N:24][CH:21]2[CH2:23][CH2:22]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:18])[C:5]=1[O:19][CH3:20]
Reactant: S=C=NC1CC1
Reactant: CI
Reactant: CCOC(=O)CC(=O)c1ccc(Br)c(OC)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CSC=NC1CC1)=C(O)c1ccc(Br)c(OC)c1F
Temperature: 0 °C
Reaction time: 18.5 h
Yield: 76.2 %

Procedure:
Sodium hydride (60% in mineral oil, 73.7 mg, 1.92 mmol) is added portionwise to a cooled (0° C.) solution containing 13 (569 mg, 1.78 mmol), cyclopropyl isothiocyanate (500 μL, 5.40 mmol), and dimethylformamide (5.0 mL). The resulting mixture was allowed to warm to room temperature with stirring overnight (18.5 h). Methyl iodide (700 μL, 11.22 mmol) is added to the resulting solution to give a precipitate within minutes. The mixture is stirred for an additional 24 h. The reaction mixture is quenched by addition of a saturated aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts are washed with brine (200 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 10% v/v ethyl acetate in methylene chloride; Rf 0.59) to give 586.0 mg (76% yield) of 14 as a viscous yellow oil. 1H NMR (CDCl3): δ 0.86 (m, 2H, c-Pr CH2), 0.89 (t, JH-H=7.0 Hz, CO2CH2CH3), 0.98 (m, 2H, c-Pr CH2), 2.52 (s, 3H, S—CH3), 3.01 (m, 1H, c-Pr CH), 3.90 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 3.94 (d, JH-F=1.5 Hz, 3H, OCH3), 6.97 (dd, JH-H=8.5 Hz, JH-F=6.5 Hz, 1H, aromatic H-6), 7.30 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, aromatic H-5), 11.91 (br, 1H, OH). 19F{1H} NMR (CDCl3): 8-130.4 (s). 13C{1H} NMR (CDCl3): δ 8.6 (c-Pr CH2), 13.5 (CO2CH2CH3), 18.1 (S—CH3), 28.5 (c-Pr CH), 60.3 (CO2CH2CH3), 61.4 (d, JC-F=5.0 Hz, OCH3), 104.2 (—C(OH)═C(CO2CH2CH3)—), 118.3 (d, JC-F=2.5 Hz, aromatic C-4), 123.4 (d, JC-F=3.5 Hz, aromatic C-6), 127.6 (d, JC-F=3.5 Hz, aromatic C-5), 131.9 (d, JC-F=14.5 Hz, aromatic C-1), 145.1 (d, JC-F=13.5 Hz, aromatic C-3), 152.6 (d, JC-F=253.0 Hz, C-2), 167.7 (CO2CH2CH3), 174.5 (—N═C(S—CH3)—), 185.5 (—C(OH)═C(CO2CH2CH3)—). LCMS m/z calcd for C17H1979BrFNO4S ([M]+) 431. Found 432 ([M+H]+). HRMS m/z calcd for C17H2079BrFNO4S 432.0280 ([M+H]+). Found 432.0276.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:20][C:19]=1[OH:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:20][C:19]=1[O:38][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A mixture of 1.0 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine, 1.37 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 0.67 g of potassium carbonate and 5 ml of N,N-dimethylformamide was stirred for 1 hour at room temperature, then at 50° C. for 30 minutes. The resulted residue was added to ice water, extracted with ethyl acetate, and organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.25 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:14][CH2:13][CH2:12][S:9]1(=[O:11])=[O:10])[CH:2]=[CH2:3].[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][CH:18]([SiH3:24])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:19][CH:18]([SiH2:24][CH2:3][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:14][CH2:13][CH2:12][S:9]1(=[O:10])=[O:11])[O:17][Si:16]([CH3:26])([CH3:25])[CH3:15]
Reactant: C[Si](C)(C)OC([SiH3])O[Si](C)(C)C
Reactant: C=CCOCCOC1CCCS1(=O)=O
Solvent: Cc1ccccc1C
Product: C[Si](C)(C)OC(O[Si](C)(C)C)[SiH2]CCCOCCOC1CCCS1(=O)=O
Yield: 134.7 %

Procedure:
A 500 ml three neck round bottom flask equipped with a magnetic stirrer, condenser, additional funnel, and pot thermometer was charged with 165.0 g (0.75 mol) of allyloxyethoxy sulfolane under appositive pressure of nitrogen. After heating to 80° C.-90° C., 61.2 g (0.28 mol) of bis(trimethylsiloxy)methylsilane was added, followed by 1 ml of Pt(0)-divinyltetramethyldisiloxane solution in xylene (2 wt % Pt). The pot temperature rose from 86° C. to approximately 102° C. The rest of 122.4 g (0.55 mol) of bis(trimethylsiloxy)methylsilane was added while maintaining a pot temperature of between 86° C.-106° C. The mixture was then maintained at a temperature between 86° C.-96° C. for 16 h and was distilled. 167.0 g (50.3%) pure bis(trimethylsiloxy)methylsilylpropoxyethoxy sulfolane was obtained. The pure product had a boiling point of 194° C.-200° C. at 0.4 mm Hg and a density of 1.412 at 25° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15](=[O:18])([OH:17])[OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].N1C=C[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15]2(=[O:16])[O:17][CH2:24][CH2:23][CH2:22][O:18]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
Oxalyl chloride (22.09 g) was added dropwise to a mixture of 4-nitrobenzylphosphonic acid (17.99 g), pyridine (13.76 g) and tetrahydrofuran (500 ml) at -78° C. After this mixture was stirred at -78° C. for 30 minutes and then at room temperature for 1.5 hours, the insoluble solid was filtered off. The filtrate was concentrated under reduced pressure; the residual oil was dissolved in tetrahydrofuran (500 ml). To this solution, a solution of 1,3-propanediol (2.58 g) in acetonitrile (30 ml) was added dropwise at -78° C. over a period of 15 minutes. Pyridine (5.62 g) was then added dropwise at the same temperature over a period of 5 minutes; the mixture was stirred at room temperature for 15 hours. After the insoluble substance was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (10:10:1, v/v) to yield 2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide (5.62 g, 26%), which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 144°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[Si:13]([O:20][CH2:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(C(C)C)C(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][C:22]([CH3:35])([CH3:36])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[O:11])=[CH:4][C:3]=1[F:12]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(Br)c(F)c2)cc1C(F)(F)F
Yield: 61.4 %

Procedure:
A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol), 4-(3-((tert-butyl dimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (78 mg, 0.215 mmol), N-ethyl-N-isopropylpropan-2-amine (83 mg, 0.644 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (49.3 mg, 0.322 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (61.7 mg, 0.322 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=3/1) to yield 2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.132 mmol, 61.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.15 (dd, J=9.7, 1.8 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 3.62 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 0.86 (s, 9H), 0.76-0.69 (m, 6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]3[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]3[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:34][CH3:35])=[O:21])=[CH:16][CH:15]=3)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCO
Reactant: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Reaction time: 72 h

Procedure:
A suspension of (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purin-8-yl)cinnamic acid (4.00 g, 10.4 mmol) (Example 6) and concentrated sulfuric acid (1 ml) in absolute ethanol (1.5L) was refluxed for 2 hours with slow distillation of 75 ml of vapor. Reflux was continued for 3 days with exclusion of moisture with 50 ml distillate being removed during the final 4 hours. The cooled suspension was filtered to yield ethyl (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purin-8-yl)cinnamate as a pale yellow solid. mp >300° C. Analysis for (C22H26N4O4). C,64.38; H,6.38; N,13.65. Found: C,64.34; H,6.43; N,13.63.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=[O:5].[OH-].[NH4+:20]>O1CCCC1>[C:6]1([C:4](=[O:5])[C:3]([NH2:20])=[O:2])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of (5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (0.50 g, 2.06 mmol) in 10 mL of tetrahydrofuran at 0° C. was added concentrated ammonium hydroxide (2 mL). The bath was removed and the mixture stirred 3 hours. After diluting with 20 mL of water, the suspension was filtered, washed with 10 mL of water followed by 10 mL of diethyl ether, and dried under reduced pressure to provide 0.403 g (86%) of the desired compound as a light yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:37])[CH3:36].N1C=CC=CC=1>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)[CH:25]=3)[NH:1][C:35](=[O:37])[CH3:36])=[CH:4][CH:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of 1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (80 mg, 0.175 mmol), acetyl chloride (15 μL, 0.211 mmol) and dichloromethane (1.5 mL) is stirred at room temperature. Pyridine (50 μL, 0.62 mmol) is added and the mixture is stirred at room temperature 24 hr. An additional portion of acetyl chloride (20 μL, 0.28 mmol) is added and the reaction is stirred an additional 24 hr. The reaction mixture is purified as is via reversed phase C18 preparative chromatography eluting with 4:6 acetonitrile:water (0.1% trifluoroacetic acid) to 8:2 acetonitrile:water (0.1% trifluoroacetic acid) to give the title compound (53 mg, 61%), as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.92 (d, 1H), 8.03 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.36-7.61 (m, 6H), 6.73 (d, 1H), 6.23 (d, 1H), 5.25 (s, 2H), 2.59-2.62 (m, 5H), 1.97 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1=498.