Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([Li])(CC)C.[O:17]1[C:21]2([CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[O:17]1[C:21]2([CH2:22][CH2:23][CH:24]([CH:27]3[CH2:32][CH2:31][C:30]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:11])[C:6]=4[F:10])([OH:33])[CH2:29][CH2:28]3)[CH2:25][CH2:26]2)[O:20][CH2:19][CH2:18]1
Reactant: CCOc1cccc(F)c1F
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
3-Ethoxy-1,2-difluorobenzene (s65) (10.0 g) and THF (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane-cyclohexane; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s66) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)-cyclohexanol. The compound was mixed with p-toluenesulfonic acid (0.68 g) and toluene (200 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (0.3 g) was added to the purified product and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:9 by volume) to give 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (s67) (7.7 g). The yield based on the compound (s65) was 35.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([Cl:19])[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:14]=[C:15]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[CH:22]3)[CH:16]=[C:17]([Cl:19])[N:18]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(Nc1nc(Cl)cc(Cl)n1)c1cccc([N+](=O)[O-])c1
Product: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4,6-dichloropyrimidine and benzimidazole according to the procedure described in EXAMPLE 306, Step B.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:8][C:7]=12
Reactant: CCCCCCCCCC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: CCCCCCCCCc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and decanoic acid (0.35 g, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.38 g, 72%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.16 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.03 (t, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.25-2.0 (m, 14H), 0.90 (t, 3H, J=7.8 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6].Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:13][CH2:12][C:11]2[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][O:9][C:10]=2/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:24][CH:25]=1
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: CCCCc1noc(/C=C/c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1noc(/C=C/c2ccccc2)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a suspension of sodium hydride (170 mg, 4.24 mmol) in THF (7 mL) at 0° C. was added a solution of [3-butyl-5([E]-styryl)-isoxazol-4-yl]-methanol (993 mg, 3.86 mmol) in THF (17 mL) and the mixture was stirred for 30 min at room temperature. The reaction mixture was cooled to 5° C. and a solution of methyl 6-bromonicotinate (1.0 g, 4.6 mmol) in THF (17 mL) was added dropwise. The mixture was stirred at room temperature for 2 days, poured over ice and stirred for 5 min. The mixture was extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to a yellow oily solid. The crude material was purified by flash chromatography (silica gel, heptane:ethyl acetate 1:0 to 3:2) to afford the title compound (1.17 g, 77%) as an orange semisolid. MS: m/e=393.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A stirred solution of 1.29 g of the ester from Example 20 (step A) in 3.5 ml of methylene chloride was treated with 3.5 ml of trifluoroacetic acid and the solution stirred 2.5 hours at ambient temperature. The solution was then concentrated under a stream of nitrogen and the residue dissolved in methylene chloride/diethyl ether. The solution was washed 2 times with saturated aqueous sodium carbonate solution and the organic phase was then dried with sodium sulfate and filtered. Concentration under vacuum provided 919 mg of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:5][O:4]1
Reactant: CC(=O)OC(C)=O
Reactant: COC1CCC(CO)CO1
Solvent: c1ccncc1
Product: COC1CCC(COC(C)=O)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
2-Methoxy-5-hydroxymethyltetrahydropyran (0.91 g) was dissolved in pyridine (10 ml), and the solution cooled to 5° C. Acetic anhydride (3.15 ml) was added thereto, and the mixture stirred at the same temperature For 1 hour, and then at room temperature overnight. After removing pyridine by evaporation under reduced pressure, the residue was purified on a silica gel column (eluent: n-hexane/ethyl acetate=1/2) to obtain the desired product (0.93 g, 80.0%) as pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.Cl.Cl.[NH2:24][CH2:25][C:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[NH2:32][C:26]1([CH2:25][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCC1(N)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of 4-chloro-3-nitroquinoline (25.0 g, 120 mmol) and triethylamine (84 mL, 599 mmol) in dichloromethane (500 mL) was added 1-(aminomethyl)cyclohexanamine dihydrochloride (36.2 g, 180 mmol). The reaction was allowed to warm to rt and stirred for 20 h. The reaction was transferred to a separatory funnel and washed with water (200 mL). The water was back-extracted with dichloromethane (2×500 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield N-[(1-aminocyclohexyl)methyl]-3-nitroquinolin-4-amine as a yellow solid (35.5 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([Cl:20])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([Cl:20])[S:17][C:15]=2[N:16]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].C(N(CC)CC)C.[C:22]([O:26][C:27](OC([O-])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3](=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Oc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
5.6 g (30 mmol) of 2-cyano-3-(4-hydroxyphenyl) acrylic acid dissolved in 40 ml acetonitrile were stirred with 4.6 ml (33 mmol) of triethylamine until a clear solution was obtained. 0.2 g (4 mmol) 4-dimethylaminopyridine and 7.3 g (33 mmol) tert-butylpyrocarbonate were then added to the clear solution. After 2 hours reaction (the solution is at that point colourless), the solution was reduced to its half volume and washed with 200 ml of a cold 5% citric acid solution.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([C@:20]([C@:24](CC1C=CC=CC=1)([C@@:26](CC1C=CC=CC=1)([C@@H:28]([CH:30](CC1C=CC=CC=1)[OH:31])[OH:29])[OH:27])[OH:25])([OH:23])[CH:21]=[O:22])C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:21]([C@@H:20]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23])=[O:22])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=C[C@@](O)(Cc1ccccc1)[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)[C@H](O)C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)ccc1O

Procedure:
Vanillic acid having a benzyl-protected hydroxyl group at the 4 position and 2,3,4,6-tetrabenzyl glucose having benzyl-protected hydroxyl groups at positions other than the 1 position (Sigma-Aldrich) were condensed in a DMF solvent (at a reaction temperature of 60° C.) using the following condensing agents: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, Kokusaikagaku Co., Ltd.), 4-dimethylaminopyridine (DMAP, Tokyo Kasei Kogyo), and triethylamine (Et3N, Wako Pure Chemical Industries, Ltd.). The obtained condensate was a mixture comprising a anomer and β anomer at a ratio of 1:2. The condensate was purified using an open column (at different concentration ratios of hexane:ethyl acetate=6:1 and 5:1). A unreacted starting material was removed. The yield was found to be 84%: Molecular MS [M+Na]+ m/z 803.14, 1H NMR (300 MHz, CDCl3): δ7.60 (1H, dd, H-6), 7.59 (1H, d, H-2), 7.45-7.26 (60H, m, H-benzylic CH2), 6.90 (1H, d, H-5), 6.55 (1H, d, H-Glc1α, J=3.21), 5.84 (1H, d, H-Glc1β, J=7.65), 5.25 (10H, s, H-benzylic CH2), 4.96-3.56 (94H, m, CH3, H-Glc).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (0.6 ml), and a solution of 4-fluorobenzoyl chloride (0.8 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:36])([CH3:23])[CH:33]=[C:32]2[CH3:34]
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4c(c3)C(C)=CC(C)(C)N4)ncnc2cc1OCC1CCN(C)CC1
Yield: 73.7 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (140 mg, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24]>CC(C)=O>[C:1]([C:4]1[C:5]([O:14][CH:22]2[CH2:27][CH2:26][O:25][C:23]2=[O:24])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C1OCCC1Br
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(C)=O)c1OC1CCOC1=O

Procedure:
To a mixture of methyl 3-acetylsalicylate (5.8 g) and potassium carbonate (10.4 g) in acetone (200 ml) was added α-bromo-γ-butyrolactone (12.5 g) under stirring, and the mixture was refluxed for 11 hours. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on silica gel eluting with chloroform. By the above procedure, there was obtained α-[(6-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone as pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])cn1

Procedure:
To a suspension of 36.9 g of 2-chloro-5-nitropyridin-4-amine (example E6) in 500 ml methanol were added 250 ml of a freshly prepared solution of sodium methoxide in methanol (5.7 g sodium) and the reaction mixture was refluxed for 12 h. About 500 ml methanol were distilled off and 500 ml of water were added. The resulting precipitate was filtered, washed with ice water and dried under vacuum to the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:9])[C:3](=[N:7]O)[C:4](=O)[CH3:5].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17]>C(#N)C>[CH3:5][C:4]1[NH:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[N:7][C:3]=1[C:2](=[O:9])[CH3:1]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: NCc1ccccn1
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccccn2)[nH]c1C
Temperature: -10 °C
Yield: 35.8 %

Procedure:
A mixture of 6.5 g (0.05 mole) of 2,3,4-pentanetrione 3-oxime and 6.0 g (0.055 mole) of 2-pyridylmethylamine in 125 ml of acetonitrile was stirred and refluxed as described in Example 1. Cooling at -10° C. gave a precipitate which was recrystallized from acetonitrile to give 3.6 g of the product of the Example as a yellow solid, mp 145°-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 22 (80 g, 406 mmol) and (4-nitrophen-oxy)-acetic acid-2-hydroxyethyl ester 23 (80 g, 332 mmol) in anhydrous dichloro-methane (2 L) under nitrogen atmosphere was added a solution of 1,3-di-cyclohexyl carbodiimide (128 g, 620 mmol) in anhydrous dichloromethane (750 ml) drop wise. The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 24. The crude 24 was purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to get pure 24 (75 grams, 54%) as a white powder with an m.p. between 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]#[N:12])(=[O:21])=[O:20])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)cnc1N
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1C#N

Procedure:
Prepared by method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-cyanobenzenesulphonyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=O)[CH:6]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][C:33](=[O:35])[CH:34]=[C:8]3[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one (60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under an atmosphere of dry N2. To this solution was added 180 mL of triethylamine (NEt3), 50 mL of acetic anhydride (AC2O) and 1.60 g (13.0 mMol) of 4-dimethylaminopyridine (DMAP). The reaction mixture was then heated to reflux and stirred at this temperature for 20 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected via suction filtration. The solid was washed with ethyl ether (Et2O) and dried under vacuum to give of the titled compound (63 g) which was used without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38]>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:9]=[C:10]([O:21][C:29]2[C:30]([N+:37]([O-:39])=[O:38])=[CH:31][CH:32]=[C:33]([F:36])[C:34]=2[F:35])[CH:11]=[C:12]([C:14]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(C)(C)NC(=O)c1cc(O)cc(C(=O)NC(C)(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A 22 L round-bottom flask was charged with 3,5-bis-tert-butylcarbamoyl-phenol (20, 360 g, 1.23 mol) and THF (12.5 L). The resulting slurry was cooled to 0° C. and potassium tert-butoxide (1.35 L, 1.0 M in THF, 1.35 mol) was added dropwise over approximately 30 min. After the addition was complete, the reaction mixture was cooled to between −30 and −35° C. and 2,3,4-trifluoronitrobenzene (239, 1.35 mol) was added dropwise over approximately 5 min. The reaction mixture was stirred at approximately −30° C. for 1 h whereupon the cooling bath was removed. The reaction mixture was then stirred for 20 h with warming to ambient temperature. A mixture of water (2.0 L) and brine (1.0 L) was added, and the reaction mixture was stirred vigorously in a 20 L extractor ball. Following removal of the aqueous phase, the organic layer was washed with additional brine (1.5 L), and the resulting THF solution was transferred to a 22 L round bottom flask for distillation. The extractor ball was rinsed with THF (500 mL). After approximately 10 L of THF had been removed by distillation, addition of isopropyl alcohol (11 L) was initiated and the distillation was continued until approximately 23 L of distillate had been collected. When the residual volume was 5 L and the pot temperature was 82° C., water (2.0 L) was added dropwise. Heating was then discontinued, and the reaction mixture was stirred overnight with cooling to room temperature. The resulting solid was filtered through a 3 L course-frit sintered glass filter funnel. The filter cake was washed with IPA/H2O (1:1, 2×600 mL) and dried in a vacuum oven (70° C., 25 Torr) to afford N,N′-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21; 488 g, 88% theory).
Reaction SMILES: [OH:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C1COCC1>[Br:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([OH:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(O)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(O)nnc12
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
The mixture of solution of 3-hydroxy-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.381 mmol) and N-bromosuccinimide (204 mg, 1.14 mmol) in THF (2 ml) was stirred in a microwave reactor at 70° C. for 10 min. The reaction mixture was filtrated and the filtrate was purified by prep LCMS to yield the desired product. LCMS calculated for C11H14BrN6O2 (M+H) 341.0; found: 341.0, 343.0.