Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.C([Sn+3])CCC>>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCCC(CC)C(=O)[O-]
Agent: CCCC[Sn+3]
Product: CC(C)CCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In a three-necked, round-bottomed flask fitted with a stirrer, thermometer, reflux condenser with a trap to collect distilled off methanol and later isooctanol and a vacuum connection are added 200 g (0.684 mole) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate, 178 g (1.37 moles, 100% excess) of isooctanol (Exxal®-8, Exxon) and 0.05 g (0.0000826 mole; 50 ppm of tin in final product) of butyltin tris-(2-ethylhexanoate) (Fascat® 9102, Elf-Atochem). The reaction mixture is subjected to a reduced pressure of 400 mm Hg and the flask is heated to 140°-150° C. Methanol begins to be evolved and is collected in the trap receiver. When the reaction mixture reaches 160° C., reflux of isooctanol is observed and becomes vigorous at 170°-180° C. while the evolution of methanol subsides. At this point, the excess isooctanol is then stripped into the trap receiver and the pressure in the system is ultimately reduced to 5 mm Hg. When all the excess isooctanol is removed, the residue in the flask is cooled under nitrogen and is the desired title compound in essentially quantitative yield (over 99% by weight).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: COC(=O)[C@H]1C[C@H](O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 85 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (2.10 g, 7.51 mmol), trans-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (1.11 g, 8.53 mmol), and PS-PPh3 (loading 2.21 mmol/g; 6.80 g, 15.0 mmol) in dry THF (80 mL), cooled by ice/water, was added DIAD (2.20 mL, 2.26 g, 11.2 mmol), then the cooling bath was removed, and the mixture was vortexed (150 rpm) overnight. The resin was filtered off and washed thoroughly with THF (≈400 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-16)→5% EtOAc in CH2Cl2 (17-40)]. Fractions 3-32 were combined, concentrated, and suspended in iPrOH (10 mL). The suspension was heated to 85° C. for 20 min and cooled to −20° C. for 2 h, the solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo. One obtained the title compound as white solid. Analytically pure material with cis/trans=50:1 had a melting point of 168-169° C. 1H NMR (CDCl3, 400 MHz): δ=2.66-2.78 (m, 2H), 2.81-2.93 (m, 2H), 3.06 (quint, J=8.7 Hz, 1H), 3.76 (s, 3H), 5.32 (quint, J=8.7 Hz, 1H), 7.68 (s, 1H), 8.60 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=30.93 (+), 34.09 (2C, −), 44.65 (+), 51.58 (Cquart), 52.19 (+), 117.07 (Cquart), 131.87 (+), 150.48 (Cquart), 150.72 (+), 152.69 (Cquart), 174.31 (Cquart). MS (ES+): m/z 391.9/393.9 (100/38) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min). C12H11ClIN3O2 (391.60): C: calc. 36.81. found 36.88/36.78; H: calc. 2.83. found 2.81/2.76; N: calc. 10.73. found 10.59/10.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[S:8][CH:9]=1
Reactant: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A solution of (2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (prepared in Example 24, 75.3 mg, 0.18 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 4 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give {2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (64.5 mg, 93.3%) as a tan oil: EI-HRMS m/e calcd for C20H25N3O3S (M+) 387.1616, found 387.1612.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].Cl[CH2:15][S:16]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:15][S:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 ml) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added drop wise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.4 g, 3 mmoles).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[O:23]=[C:24]([CH3:29])[CH2:25][C:26]([NH2:28])=[O:27]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:28]=[C:26]([OH:27])[C:25]([C:24](=[O:23])[CH3:29])=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)CC(N)=O
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)n1
Product: CSc1nccc(-c2cc(C(C)=O)c(O)nc2-c2ccc(F)cc2)n1

Procedure:
Following a similar procedure to that described in reference example 10, but starting from 3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one (obtained in reference example 20) and 3-oxobutyramide, the title compound was obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[CH2:17][O:18][CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:18][CH2:17][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1
Reactant: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H]1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-methoxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.863 g, 4.67 mmol, 1 eq) in CH2Cl2 (50 mL) was cooled to 0° C. and TFA (12 mL) was added. The reaction was stirred at room temperature for 1 hr and then poured carefully into 1 N NaOH. The pH was adjusted to basic with 2.5 N NaOH and it was extracted with CH2Cl2. The combined organics dried over sodium sulfate and concentrated to afford the title compound as a yellow oil, which was used crude in the following reaction. NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][C:26]#[C:27][C:28]([O:31][Si](CC)(CC)CC)([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][C:26]#[C:27][C:28]([OH:31])([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([OH:46])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C#CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 110.2 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyloxy-4-methyl-2-pentynyloxy)-20-methylpregna-5,7,16-triene (82 mg, 0.105 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (3 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (51 mg, quantitative) as a colorless foam.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCNCc1cc[nH]n1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1cc[nH]n1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-pyrazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyrazolylmethylamino)ethyl]guanidine, and in the procedure of Example 2(iii) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-N"-nitroguanidine.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[CH:5][N:4]=1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:9]([C:8]1[C:3]([CH2:2][N:30]([CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=2)=[N:4][CH:5]=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCOc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Reactant: CCCCc1c(CBr)ncnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCc1c(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCCO3)ncnc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine (86 mg), (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (93 mg, 0.310 mmol), and K2CO3 (195 mg, 1.4 mmol) in CH3CN (2.0 mL) is stirred at reflux for 1 h and at room temperature for 16 hours. The reaction mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the residue purified by preparative TLC, developing with 2:1 hexanes-EtOAc (+0.5% Et3N). The band containing product affords pure (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine. 1H NMR (CDCl3, 300 MHz) δ 8.98 (s, 1H), 7.42 (m, 5H), 7.19 (t, J=8.0 Hz, 1H), 6.92–6.73 (m, 6H), 4.22 (s, 4H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s, 2H), 3.60 (s, 2H), 3.54 (s, 2H), 2.70–2.64 (m, 2H), 1.41 (t, J=6.9 Hz, 3H), 1.09–0.99 (m, 2H), 0.91 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 524 [M+1].
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1N)[CH3:7].N([O-])=[O:17].[Na+]>O>[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[OH:17])[CH3:7]
Reactant: CCc1cccc(C)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cccc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To an ice-cold solution of H2SO4 (150 mL) in water (250 mL), 2-ethyl-6-methylaniline (15.0 g, 111 mmol) is added. The solution is treated with ice (150 g) before a solution of NaNO2 (10.7 g, 155 mmol) in water (150 mL) and ice (50 g) is added dropwise. The mixture is stirred at 0° C. for 1 h. 50% aq. H2SO4 (200 mL) is added and stirring is continued at rt for 18 h. The mixture is extracted with DCM, and the org. extracts are dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-6-methyl-phenol (8.6 g) as a crimson oil; LC-MS: tR=0.89 min; 1H NMR (CDCl3): δ7.03-6.95 (m, 2H), 6.80 (t, J=7.6 Hz, 1H), 4.60 (s, 1H), 2.64 (q, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[CH3:25][C:26]([NH2:30])([C:28]#[CH:29])[CH3:27]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:30][C:26]([CH3:27])([C:28]#[CH:29])[CH3:25])#[N:2]
Reactant: C#CC(C)(C)N
Reactant: N#Cc1cc(NC(=O)c2ccc(F)cc2)ccc1OCC(O)CCl
Solvent: CCO
Product: C#CC(C)(C)NCC(O)COc1ccc(NC(=O)c2ccc(F)cc2)cc1C#N

Procedure:
9 gm of 1-[2-cyano-4-(4-fluorobenzoyl-amino)phenoxy]-3-chloro-propan-2-ol were dissolved in 80 ml of ethanol, and 12.5 ml of 2-methyl-but-3-in-2-amine were added to the solution. After the mixture had been refluxed for 4 hours, the solvent was distilled off in vacuo, the residue was acidified with dilute HCl and washed with ether. The aqueous phase was made alkaline with NH4OH, the base precipitated thereby was extracted twice with ethyl acetate, and the organic phase was washed with H2O and dried over MgSO4. After the ethyl acetate had been distilled off, the crystalline residue was recrystallized twice from acetonitrile. 2.8 gm of colorless crystals of the base were isolated.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN(C=O)C>[C:16]1([NH:15][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 2-(N-Bromoacetylamino)benzoic acid from Example 79 (5.0 g, 19.37 mmol), aniline (4.51 g, 4.41 mL, 48.4 mmol) and anhyd DMF (50 mL) was heated in an oil bath at 85° C. for 4.5 h. The reaction mixture was cooled and poured into ice-water (500 mL). A solution of 5% KOH (100 mL) was added to dissolve the milky white suspension and the resulting homogenous solution was extracted with CH2Cl2 (200 mL, 2×100 mL). The combined CH2Cl2 extract was set aside and the aqueous layer was acidified to pH=3 (pH meter) with 5% HBr. The resulting precipitate was washed with 5% HBr solution and water, and then dried in a vacuum oven at 50° C. for 2 days, yielding 4.74 g (90.6%) of a white powder, mp 192.4°-192.8° C. (sealed tube); 1H NMR (DMSO-d6) 13.41 (bs, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=7.6, J=1.6, 1H), 7.59 (dt, J=8.8, J=1.6, 1H), 7.15-7.05 (m, 3H), 6.63-6.45 (m, 4H); 3.83 (s, 2H); 13C NMR (DMSO-d6) δ 170.85, 169.01, 148.11, 140.56, 134.13, 131.10, 128.94, 122.63, 119.38, 117.10, 115.96, 112.40, 48.93; MS (EI, m/z) 270.1 (M+) .
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cccnc2n1-c1ccccc1
Yield: 88.9 %

Procedure:
Method A applied to 2-chloro-3-nitropyridine (79 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as pale yellow viscous oil (93 mg, 89%). 1H NMR (DMSO) δ 2.48 (s, 3H), 7.24 (dd, 1H), 7.53-7.63 (m, 5H), 8.02 (d, 1H), 8.20 (d, 1H); 13C NMR δ 14.6, 118.3, 125.9, 127.4, 128.7, 129.3, 134.1, 134.3, 143.0, 148.7, 152.9. HRMS (FAB): cal. for C13H12N3 [M+H+]: 210.1031; found: 210.1027.
Reaction SMILES: [CH:1]([OH:40])([CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:39])([F:38])[F:37])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23])[CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4].[N:41]([CH2:44][CH2:45][CH2:46][Si:47]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])=[C:42]=[O:43]>C(C(C)=O)C>[CH:1]([O:40][C:42]([NH:41][CH2:44][CH2:45][CH2:46][Si:47]([O:48][CH2:49][CH3:50])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])=[O:43])([CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4])[CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:37])([F:39])[F:38])([F:34])[F:35])([F:31])[F:32])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23]
Reactant: CN(CC(O)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Solvent: CCC(C)=O
Product: CCO[Si](CCCNC(=O)OC(CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(OCC)OCC
Temperature: 30 °C

Procedure:
A three-necked round bottom 500 mL flask fitted with a stirrer, heating mantle, condenser, nitrogen inlet, Dean-Stark trap and thermometer was charged with [C4F9SO2N(CH3)CH2]2CHOH (204.6 g, 0.300 mol), and methyl ethyl ketone (250 g). The mixture was heated and approximately 50 g of material was removed using the Dean-Stark trap. The mixture was cooled to 30° C., and OCN(CH2)3Si(OCH2CH3)3 (74.4 g, 0.301 mol) and three drops of stannous octanoate were added. The mixture was heated at 75° C. under nitrogen for 16 hours. A clear, slightly yellow product ensued. Analysis of the product was consistent with [C4F9SO2N(CH3)CH2]2CHOC(O)NH(CH2)3 Si(OCH2CH3)3.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=2)[CH:35]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29].[NH2:49][C:50]1[N:59]=[C:58]([N:60]2[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]2)[C:57]2[C:52](=[CH:53][C:54]([C:67](O)=[O:68])=[CH:55][CH:56]=2)[N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:49][C:50]1[N:59]=[C:58]([N:60]2[CH2:61][CH2:62][N:63]([CH3:66])[CH2:64][CH2:65]2)[C:57]2[C:52](=[CH:53][C:54]([C:67]([NH:26][CH:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=4)[CH:35]=3)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:68])=[CH:55][CH:56]=2)[N:51]=1
Reactant: CN(C)C(=O)C(N)Cc1cccc(Oc2cccc(C#N)c2)c1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4cccc(Oc5cccc(C#N)c5)c4)C(=O)N(C)C)ccc23)CC1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of 2-amino-3-[3-(3-cyanophenoxy)phenyl]-N,N-dimethylpropanamide HCl salt (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=2) to give the desired compound (0.004 g, 10%) as a white amorphous solid TFA salt. 1H NMR (400 MHz, DMSO): δ 7.98 (d, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.14 (m, 2 h), 7.03 (s, 1H), 6.86 (d, 1H), 5.08 (m, 1H), 4.56 (m, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 3.22 (m, 2H) 2.99 (m, 5H), 2.82 (s, 3H), 2.78 (s, 3H); Analytical LCMS (M+H)+: m/z=579.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([OH:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2]([O:1][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=1[O:13][C:20]1[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1c(O)cc(C)cc1O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1c(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(C)cc1Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using procedure as in Example 10, a reaction of methyl 2,6-dihydroxy-4-methylbenzoate (50 mg, 0.274 mmol), NaH (24 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (159 mg, 2 equiv.) afforded 4-methyl-2,6-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester. 1HNMR (360 MHz, DMSO-d6) δ 8.80 (d, J=2.2 Hz, 2H), 8.32 (dd, J=2.2 & 9.0 Hz, 2H), 7.48 (d, J=2.7 Hz, 2H), 7.44 (s, 2H), 3.50 (s, 3H, OCH3), 1.23 (s, 3H, CH3). MS-APCI (negative mode) m/z 686.6 [M+−2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](SC2C=CC=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](=[O:27])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Yield: 88.4 %

Procedure:
To a mixture of 3-chloro-4-methoxyphenylboronic acid (0.87 g, 4.67 mmol), ligand TFP (0.14 g, 0.6 mmol), Pd2dba3 (0.29 g, 0.31 mmol), copper (I) thiophene-2-carboxylate (0.89 g, 4.7 mmol) was added a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.1 mmol) in 10 mL of THF while purging with N2 at 50° C. After 18 hours the reaction mixture was diluted with ethyl acetate, filtered through celite then concentrated in vacuo. Purification by flash chromatography gave the title compound (1.02 g, 2.74 mmol). MS (ESI) m/z 354.0 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.42 min.