Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)(=[O:4])=[O:3].[N:13]([O-])=[O:14].[Na+].O.Cl>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([N:13]=[O:14])[C:7]([CH3:12])([CH3:11])[CH2:6]1)(=[O:3])=[O:4]
Reactant: O=N[O-]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CN(S(C)(=O)=O)CCN1N=O

Procedure:
A mixture, cooled to 0°-5° C., of 45 g of 4-methanesulphonyl-2,2-dimethylpiperazine, 19.3 g of sodium nitrite, 250 ml of water and 100 ml of methanol is adjusted to pH 1.0 using conc. HCl and stirred at a gradually increasing temperature for 12 hours. The precipitate is filtered off with suction, washed with water and dried in vacuo.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:27]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[C:29](=[O:35])[CH2:28]2.[ClH:36]>C1CCCCC1.O1CCCC1>[ClH:36].[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:29]3([OH:35])[CH:30]4[CH2:33][CH2:34][N:27]([CH2:32][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: O=C1CN2CCC1CC2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(C3(O)CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of sec-butyllithium in cyclohexane (7.4 ml, 1.3M) was added dropwise, with stirring, to a solution of 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (2.9 g) in dry tetrahydrofuran (30 ml) under an atmosphere of argon at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (0.9 g) in dry tetrahydrofuran (12 ml) was then added over a period of 2 minutes. The mixture was stirred at -78° C. for a further 30 minutes and the mixture then allowed to warm to room temperature over 2 hours. Aqueous 2M hydrochloric acid (18 ml) was added to the reaction mixture, whilst keeping the temperature of the reaction mixture below 10° C. The aqueous layer was separated and washed with diethyl ether (2×20 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH 14. The mixture was extracted with warm ethyl acetate (50° C.) and the ethyl acetate phase separated, dried (Na2SO4) and evaporated. The residue was dissolved in dry tetrahydrofuran (20 ml) and added to a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1.6 ml, 1.0M). The mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, an excess of saturated ethereal hydrogen chloride solution was added to precipitate a solid which was crystallised from methanol/ethyl acetate to give as a colourless solid, 3-(4'-hydroxybiphenyl-4-yl)-3-hydroxy-quinuclidine hydrochloride (0.93 g), m.p. 270°-271° C., microanalysis, found: C, 66.5; H, 6.5; N, 4.1%; C19H21NO2.HCl.0.66H2O requires: C, 66.5: H, 6.8: N, 4.1%; NMR ([CD3 ]2SO): 1.4-1.6(1H, m), 1.7-1.9(2H, m), 2.3-2.4(2H, m), 3.1-3.4(5H, m), 3.8-3.9(1H, d), 5.9(1H, s), 6.9-7.5(4H, d of d), 7.6(4H, s), 9.6(1H, s); m/Z 296 (M+H).
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.S(Cl)([Cl:14])(=O)=O.O.C(Cl)(Cl)Cl>ClCCl>[Cl:14][CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2 g of methyl 3-cyclopropyl-3-oxopropanoate in 20 ml of dichloromethane was added dropwise 1.24 ml of sulfuryl chloride under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water under ice-cooling, and chloroform was further added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.48 g of methyl 2-chloro-3-cyclopropyl-3-oxopropanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[N:14]1C=CC=C[CH:15]=1>C(O)(=O)C>[CH3:1][C:2]1[C:7]2[C:8](=[O:9])[NH:14][CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: c1ccncc1
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)NCC(=O)N2

Procedure:
6-Methylisatoic anhydride (10.0 g, 56 mmol) ethyl glycinate hydrochloride (9.77g, 1.25 equiv.) and anhydrous pyridine (200 mL) were combined and heated under reflux 3.5 h in a nitrogen atmosphere. The pyridine was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in acetic acid (15 mL) and heated under reflux for 6 h. The volatiles were removed under reduced pressure to give a residue which was triturated methanol and filtered to recover 3.63 g of 6-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione as a yellow solid. The methanol filtrate was evaporated and acetic acid (200 mL) was added to the residue. The brown solution was heated under reflux overnight. The reaction mixture was cooled and the volume of acetic acid was reduced to half its volume under reduced pressure. Upon cooling, a solid precipitated which was collected. A second crop of 6-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (4.7 g) was obtained as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C#N)cc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-chloro-4-methylbenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 90-95° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 700 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3-chloro-4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (4.7 g, 88%) was used in the next reaction without further purification: mp (DSC) 179° C. Anal. Calc'd. for C15H15N2SO2Cl: C, 55.81, H, 4.68, N, 8.68. Found: C, 55.65, H, 4.63, N, 8.59.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:25][CH2:26][N:22]([C:2]3[C:3]([CH:8]4[CH2:11][N:10]([C:12]5[CH:21]=[CH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[N:13]=5)[CH2:9]4)=[N:4][CH:5]=[CH:6][N:7]=3)[CH2:23]2)[CH:28]=1
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Reactant: c1cncc(C2CCNC2)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1cncc(C2CCN(c3nccnc3C3CN(c4ccc5ccccc5n4)C3)C2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a 3 mL vial was added 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.04000 g, 0.135 mmol), 3-(pyrrolidin-3-yl)pyridine (commerically available at Array Biopharma, 0.040 g, 0.270 mmol), and triethylamine (commerically available at Sigma Aldrich, 0.038 ml, 0.270 mmol) in DMSO (Solvent Volume: 0.449 ml) and the reaction was stirred at 110° C. overnight. Upon completion, the reaction was filtered into a 24 well plate and purified by reverse phase purification using the following conditions: (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD; Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH; Column: Phenomenex Gemini-NX C18 110A 5 um 21×100; Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 mins.)
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12](Cl)=[O:13])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=1.[Mg].Cl>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)=[O:13])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H]1CC[C@H](CC(=O)c2cc(F)c(F)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trans-4-butylcyclohexylacetyl chloride (25 g, 0.115 mol) was dissolved in dry tetrahydrofuran (30 ml), followed by cooling the solution down to 0° C., adding iron acetylacetonate (0.81 g), agitating the mixture, adding a solution of a Grignard reagent prepared from 1-bromo-3,4,5-trifluorobenzene (25 g, 0.115 mol) and metallic magnesium (2.8 g, 0.115 mol), in tetrahydrofuran, at a rate at which the reaction temperature did not exceed 10° C., reacting the mixture at 5° C. or lower for 2 hours, adding 6N hydrochloric acid (10 ml) and water (100 ml) to the reaction solution, extracting a deposited oily substance with n-heptane (100 m(), washing the extract solution with a dilute alkali aqueous solution, washing with water till the washing water became neutral, drying over anhydrous sodium sulfate, distilling off n-heptane from the n-heptane solution, and recrystallizing the residue from ethyl alcohol to obtain 1-(trans-4butylcyclohexylacetyl)-3,4,5-trifluorobenzene (21.0 g). C-I point: 42.8° C. This compound was dissolved in ethyl acetate (100 ml), followed by adding 5% Pd supported on barium sulfate (0.5 g), subjecting the mixture to a catalytic reduction at 25° C. under 3 atm till hydrogen absorption ceased, filtering off the catalyst after completion of the reaction, and subjecting the reaction solution to a suitable purification treatment to obtain 1-(trans-4-butylcyclohexyl)-2-(3,4,5-trifluorophenyl)ethane (18.0 g). C-I point: 8.4° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11].[H-].[Na+].Br[CH2:19][O:20][CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11]
Reactant: CON(C)C(=O)Cc1ccc(O)cc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(CC(=O)N(C)OC)c(Br)c1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
A solution of 2-(2-bromo-4-hydroxyphenyl)-N-methoxy-N-methylacetamide (1.37 g) in THF (5 mL) was slowly added to a suspension of sodium hydride (0.22 g) in THF (30 mL) at 0° C. After stirring for 10 min, bromo(methoxy)methane (1.25 g) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 hr. The mixture was poured into water and extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (1.34 g).
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:14])[C:11](O)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:17])=O>>[CH2:1]([O:9][CH:10]([CH3:14])[C:11]([Cl:17])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOC(C)C(=O)O
Product: CCCCCCCCOC(C)C(=O)Cl

Procedure:
10 ml of thionyl chloride was added to 2.0 g of α-octyloxypropionic acid, and the mixture was refluxed under heat for 2 hours. Then, excess thionyl chloride was distilled off to obtain α-octyloxypropionic acid chloride. 20 ml of dry pyridine was added thereto, and a solution of 5.0 g of p-hydroxybenzoic acid dissolved in 40 ml of dry pyridine was further added. After the addition, the mixture was refluxed for 2 hours, charged into ice water, and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 4-α-octyloxypropanoyloxybenzoic acid.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][NH:22][CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:26][CH2:27][CH2:28][OH:29].CCN(C(C)C)C(C)C>CCO>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: OCCCBr
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCN(CCCO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A solution of 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol), 3-bromo-1-propanol (0.021 g, 0.15 mmol) and DIPEA (0.045 g, 0.35 mmol) in EtOH (4 mL) was stirred at 75° C. for 17 h. The reaction vessel was allowed to cool to room temperature, opened, and the volatiles were removed on a rotary evaporator. The residue was redissolved in THF (3 mL). PL-NCO resin (300 mg) was added, and the resulting suspension was stirred at room temperature for 16 h. The resin was filtered and the volatiles were removed under vacuum. The crude product was purified by HPLC to afford 2-adamantan-1-yl-N-[7-(3-hydroxy-propyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-acetamide (0.0098 g, 17%).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([B:25]4[O:29]C(C)(C)C(C)(C)[O:26]4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:3]1.COCCN(S(F)(F)[F:44])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([F:44])[CH2:3][C@H:4]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:29])[OH:26])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1c1ncc(-c2ccc(B(O)O)cc2)[nH]1
Temperature: -78 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 1-2c (1.5 g, 3.3 mmol) was added as a solid to a solution of bis(2-methoxyethyl)aminosulfur trifluoride (0.91 mL, 5.0 mmol) in 15 mL CH2Cl2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH2Cl2. Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown oil. The oil was chromatographed on silica gel with with 5% MeOH/CH2Cl2 to yield 4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenylboronic acid as a tan solid (0.46 g, 37%).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].[I-:17].[K+].S(=O)(=O)(O)O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[F:11][C:8]1[CH:9]=[CH:10][C:2]([I:17])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)ccc1I
Temperature: 100 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
The title compound was prepared from the following procedure described in Collection Czechoslov. Chem. Commun., vol. 40, p. 719 (1975). To an ice-cold mixture of 2-amino-5-fluorobenzoic acid (9.0 g, 58.0 mmol) and conc. hydrochloric acid (50 mL) was added dropwise a solution of sodium nitrite (4.42 g, 64.1 mmol) in water (10 mL). Subsequently, a solution of potassium iodide (14.5 g, 87.5 mmol) and conc. sulfuric acid (4 mL) in water (30 mL) was added at the same temperature, and the mixture was heated to 100° C. and stirred for 2 hours. After the solution was cooled to room temperature, the mixture was poured into an aqueous solution of sodium thiosulfate, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude crystals. The crystals were collected by filtration, washed with hexane/diethylether, and air dried to give the title compound (6.33 g, 41% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:12][C:3]1[C:2]([Br:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: FC(F)(F)c1cnc(OCc2ccccc2)c(Br)c1
Reaction time: 18 h
Yield: 91.3 %

Procedure:
3-Bromo-5-trifluoromethyl-2(1H)-pyridone (6.09 g, 25.2 mmol) and silver carbonate (7.18 g, 26.0 mmol) were suspended in hexane (200 mL) and treated with benzyl bromide (6 mL, 50.3 mmol). The mixture was stirred for 18 hrs, then filtered. The filtrate was concentrated and the residue purified by silica chromatography to give the product as a white solid (7.65 g, 23 mmol, 91% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+]>C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)(phenyl)methanone (4.73 g, 12.35 mmol) in ethanol (100 mL) at 0° C., sodium borohydride (1.88 g, 49.42 mmol) was added portion wise. The coolant was removed, and the reaction mixture was allowed to warm to RT and stirred for 1 hour. The reaction mixture was quenched with water (30 mL) at 0° C. and then concentrated under reduced pressure. The crude material was dissolved in DCM and washed with saturated aqueous ammonium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (4.33 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2F)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 315 (M+H)+.
Reaction SMILES: C([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][NH:7]C(=O)C)(=O)C.[ClH:20]>C(O)(=O)C>[ClH:20].[ClH:20].[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:5]([NH2:4])[CH2:6][NH2:7])=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: CC(=O)NCC(NC(C)=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(=O)O
Product: NCC(N)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4 g (0.015 mol) of N,N'-Diacetyl-1-(p-Nitrophenyl)-ethylenediamine in a mixture of 20 ml glacial acetic acid and 30 ml conc. HCl was heated at reflux for 24 hr and then cooled in ice. Upon filtration, 2.5 g (66%) of the crystalline 1-(p-Nitrophenyl)-ethylenediamine Dihydrochloride was collected. Anal. (C8H13N3O2Cl2) C, H, N were within 0.4% of theoretical.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22][C:23]([O-])=[O:24].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22][CH2:23][OH:24]
Reactant: COc1cccc([N+](=O)[O-])c1CC(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc([N+](=O)[O-])c1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diisobutylaluminium hydride (20 wt %; 2.38 g, 16.8 mmol) in toluene was added to a solution of 2-(2-methoxy-6-nitro-phenyl)acetate (1.0 g, 4.18 mmol) in tetrahydrofuran (8 mL) at −5° C. The reaction mixture was stirred at 0° C. for 1 h and then poured into 1N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL) and the separated organic phase was washed with water (2×30 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenyl)ethanol (780 mg, 94%).
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCOC(=NC#N)c1cncc(NC(C)C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (95 mg, 0.67 mmol) in DMF (1 ml) was added sodium methoxide (25 mg, 0.46 mmol) followed by a solution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (80 mg, 0.33 mmol) described in Example 11 of Experimental Example 1 in DMF (1 ml), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (26 mg, yield 27%) as colorless crystals.