Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:14][OH:15].O1C=CC=CC1=O.NC1C=CC=CC=1>ClC1C=CC=CC=1Cl.C(#N)C.O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([C:11]2[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1ccc(CO)cc1N
Agent: O=c1cccco1
Solvent: Clc1ccccc1Cl
Solvent: Nc1ccccc1
Solvent: O
Product: Cc1ccc(CO)cc1-n1c(C)cc(O)cc1=O
Temperature: 165 °C
Reaction time: 0.33 h

Procedure:
4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) and 3-Amino 4-methylbenzyl alcohol (25.0 g, 182.2 mmol) were taken up in 25 ml of 1,2-dichlorobenzene. The solution was heated to 165° C. in a 250 ml round bottom flask equipped with a J-Kem temperature controller probe, and a heating mantle. In a separate 250 ml round bottom flask 4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) was suspended in 25 ml of 1,2-dichlorobenzene and also heated to 165° C. The pyrone solution was poured into the flask containing the aniline and the reaction stirred at 165° C. for 20 minutes. The reaction was allowed to cool to room temperature. Reaction contents were washed with saturated NaHCO3 (aq.). Separated the organic and aqueous layers. Aqueous layer was made acidic with dropwise addition of concentrated HCl. The product was extracted from the acidic aqueous layer with n-BuOH. N-BuOH removed in vacuo to produce a reddish brown oil. (8.5 g, 19%). Contents carried forward to next reaction with no further purification. 1H NMR (300 MHz, CD3OD) δ 7.35 (m, 2H), 7.08 (s, 1H), 6.08 (br s, 1H), 5.81 (br s, 1H), 4.60 (s, 2H), 2.01 (s, 3H), 1.87 (s, 3H). LC/MS, tr=1.42 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 246.1131 (M+H). ES-HRMS m/z 246.1107 (M+H calcd for C14H16NO3 requires 246.1125).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(Cl)(=O)OC(C)(C)C(Cl)(Cl)Cl.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-methyl-5-nitrobenzoic acid (CAS; 101580-96-5, 15 g, 69.6 mmol) and triethylamine (11.1 mL, 80 mmol) in THF (200 mL) was added 1,1,1-trichloro-2-methylpropan-2-yl carbonochloridate (19.2 g, 80 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1 hr. The resulting white solid was filtered off through Celite®. The solid was washed by THF (20 mL). To the filtrate was added NaBH4 (3.2 g, 83 mmol) at 0° C., followed by H2O (50 mL). The mixture was stirred at 0° C. for 0.5 h, and then stirred at room temperature for 1.25 h. The reaction was quenched by half satd. KHSO4. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, and then filtered through a silica pad. The SiO2 cake was washed with EtOAc. The residue was concentrated and then triturated with heptane. The resulting solid was collected by filtration to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.11 (s, 1H), 7.47 (s, 1H), 4.68 (s, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:22]2O[CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].BrC1C=C(F)C=CC=1S(NC1C=CC2N3CCCC3CC=2C=1C(OC)=O)(=O)=O.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[CH2:24][C:22]=2[C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:16])=[O:15])[CH3:2]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@H]1CCCN21
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CC1CCCN21
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CC1CCCN21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 28) and N,N-diethyl-N—((Z)-1-tributyl-stannanylprop-1-en-3-yl)-amine (Intermediate 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: OC1CCCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a mixture of 4-bromo-2-nitrophenol (1.0 g, 4.6 mmol), cyclopentanol (600 mg, 7.0 mmol) and Ph3P (1.47 g, 5.6 mmol) in THF (50 mL) at 0° C. was portion-wise added diisopropylazodicarboxylate (1.52 g, 7.5 mmol) in THF (10 mL) and the resulting mixture was left to stir overnight at ambient temperature. Solvent removal and purification by chromatography on silica gel afforded the sub-title compound (1.24 g, 94%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccs2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 4 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiophene. The solid obtained from flash chromatography was further purified by reverse phase HPLC on a C18 column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as an off-white solid (100 mg), m/z 347 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@@:18]([CH2:36][F:37])([C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=2[F:35])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48](Br)[CH:49]=[CH2:50]>C1COCC1>[CH2:50]([CH:19]1[C@@:18]([CH2:36][F:37])([C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=2[F:35])[N:17]=[C:16]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[C:21]([CH3:23])([CH3:22])[S:20]1(=[O:25])=[O:24])[CH:49]=[CH2:48]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1[C@@](CF)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (2.79 g, 5.10 mmol) in THF (30 mL) at −78° C. under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide, (7.65 mL, 7.65 mmol, 1M in THF) dropwise. The reaction mixture was stirred at −78° C. for 1 h and then allyl bromide (1.77 mL, 20.41 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 h and quenched by the addition of satd. aqueous NH4Cl at −78° C., then allowed to warm to RT and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography on a 80 g RediSep Gold column using a 0-30% EtOAc/hexanes gradient to afford tert-butyl N-[(3S)-2-allyl-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (2.0 g, 67%) as an off-white solid and a mixture of cis and trans (2:1) isomers. LC/MS (ESI+) m/z=610 (M+Na).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)S(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>O1CCOCC1.Cl>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([CH:3]=[CH:4][N:5]=[CH:16]2)=[CH:21][CH:20]=1
Reactant: COc1cccc(CN(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2ccncc2c1

Procedure:
17.8 g (45 mmol) of N-(2,2-dimethoxyethyl)-N-(3-methoxybenzyl)-4-methylbenzenesulfonamide was dissolved in 250 ml of dioxane and 70 ml of 6 N hydrochloric acid. After heating under reflux for 5 hours, the product was treated with ethyl acetate as the extracting solvent in an ordinary manner to obtain the crude product, which was purified according to the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[N:9][NH:10][CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cl-].[NH4+].C(OCC)(=O)C.[Cu]I>[CH3:11][N:10]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[N:9]1
Reactant: CNN=Cc1ncccc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1ncc2ncccc21
Temperature: 120 °C
Yield: 16.4 %

Procedure:
N-[1-(3-Bromo-pyridin-2-yl)-methylidene]-N′-methyl-hydrazine (5.7 g, 26.63 mmol), copper (I) iodide (507 mg, 2.66 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (76 mg, 0.533 mmol) and potassium carbonate (7.36 g, 53.25 mmol) are suspended in 1-methyl-2-pyrrolidinone (20 mL) and heated at 120° C. for 3 h. The mixture is diluted with saturated ammonium chloride solution and ethyl acetate. The resulting emulsion is filtered, the phases separated and the organic phase washed with brine, dried and volatiles evaporated under reduced pressure. The residue is redissolved in ethyl ether, washed with brine and the solvent removed. The residue is purified by flash chromatography (0-60% EtOAc in cyclohexane) to give 1-methyl-1H-pyrazolo[4,3-b]pyridine (580 mg, content 85%, 14%)
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cncc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cncc(CCl)c1
Reaction time: 0.33 h
Yield: 9.6 %

Procedure:
Add thionyl chloride (1 mL) to a solution of 5-hydroxymethyl-nicotinonitrile (45 mg, 0.34 mmol, 1 equiv) in anhydr CH2Cl2 (1 mL). After 20 min, basify the reaction with satd aq NaHCO3 (12 mL). Extract this mixture with Et2O (2×5 mL). Dry the combined organic layers (anhydr MgSO4) and rotary evaporate (40° C.) to yield 4.9 mg (9.6%) of 5-chloromethyl-nicotinonitrile as a yellow film. MS (m/z): 152.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28]C(=O)C)[CH:26]=2)[N:21]=[CH:20][N:19]=1.CC(O)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([OH:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.9 g, 16.62 mmol) and acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (4.62 g, 18.28 mmol) were dissolved in a 1:1 mixture of DCE:t-BuOH (50 mL). The reaction mixture was refluxed for 19 hours and then cooled to room temp. Solvent was removed via rotovap. The crude residue was then suspended in MeOH (80 mL) and NH4OH (8 mL, 30% in water) was added to the mixture. Stir for 15 hours at room temp. The reaction was heated to 100° C. and stirred for 1 hour. Cool to 0° C. and product was isolated by filtration and washed with cold MeOH to give 5 g (12.2 mmol, 67% over two steps) of desired product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2].[O:14]1[CH:18]=[CH:17][C:16](CO)=[CH:15]1>C1(C=CC(O)=CC=1)O.C([O-])(=O)C.[Ca+2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.CO>[CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH2:13][C:16]1[CH:17]=[CH:18][O:14][CH:15]=1)=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2]
Reactant: OCc1ccoc1
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC1CC1(C(=O)OC)C(=O)OCc1ccoc1
Yield: 57.4 %

Procedure:
Dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (79.5 g; 0.432 mol) was combined with 21.2 g (0.216 mol) (3-furyl)carbinol and heated to 165°-183° C. in the presence of 1.0 g hydroquinone, 1.0 g calcium acetate and 0.75 g dibutyltin diacetate. When the transalcoholysis was essentially complete, as determined by the amount of methanol recovered, heating was terminated. Gas chromatographic analysis of the reaction mixture confirmed that essentially all of the (3-furyl)carbinol was consumed. The reaction mixture was diluted with an equal volume of ethyl ether, filtered to remove insoluble catalyst residue and vacuum distilled to recover 31 g (57.4% yield) crude methyl (3-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 97°-105° C. at 0.018 mm Hg. Infrared and nuclear magnetic resonance spectra were consistent with the desired structure.
Reaction SMILES: [C:1]1([Mg]Br)[C:8]([CH3:9])=[CH:7][C:5]([CH3:6])=[CH:4][C:2]=1[CH3:3].[Li+].[Cl-].[Mg].BrC1C(C)=CC(C)=CC=1C.[N:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])=[N+:26]=[N-:27]>C1COCC1>[C:2]1([CH3:3])[CH:4]=[C:5]([CH3:6])[CH:7]=[C:8]([CH3:9])[C:1]=1[N:27]=[N:26][NH:25][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36]
Reactant: Cc1cc(C)c(N=[N+]=[N-])c(C)c1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A THF solution of MesMgBr.LiCl is first prepared by an adaptation the procedure of Knochel et al. To a stirred suspension of magnesium turnings (0.72 g, 30 mmol) and anhydrous LiCl (1.26 g, 30 mmol) in anhydrous THF (40 mL) is added 2-bromomesitylene (5.05 mL, 33 mmol). The exothermic reaction initiates slowly and is allowed to stir overnight at room temperature. To the resulting mixture, which is cooled to 0° C., is added 2-azidomesitylene (4.59 g, 28.5 mmol). Stirring is continued for 1 hour at 0° C., and then an additional 1 hour while allowing to warm to room temperature. The reaction mixture is quenched by pouring the contents into water. A minimum of aqueous NH4Cl is added to neutralize the pH, and the organic products are extracted with Et2O. After washing the combined organic layers with brine, solvents are evaporated at room temperature under reduced pressure to afford a crude product that is recrystallized from Et2O-MeOH to afford 8b (7.41 g, 92%) as off-white needles over 2 crops. 1H-NMR (CDCl3, 300 MHz): δ=9.14 (br s, 1H), 6.93 (br s, 4H), 2.32-2.30 (br m, 18H). M.p.: 92-94° C. (dec). Characterization data for 8b are consistent with literature values.
Reaction SMILES: CN1CCN=C1C1C=CC([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:35][N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH2:47][CH2:46][N:45]([NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])[CH2:44][CH2:43]2)[CH2:40][CH2:41]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(NC(=O)C(NC(=O)Nc3ccc(Cl)cc3)c3ccccc3Br)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 77, 30 mg, 0.078 mmol), 1-(1-methylpiperidin-4-yl)piperazine (purchased from Oakwood products, 21 mg, 0.11 mmol) and TEA (0.0-44 mL, 0.31 mmol) in DMF (3 mL), BOP (69 mg, 0.16 mmol) was added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (39 mg). MS 548.3 and 550.3 (M+H, Cl+Br pattern).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][OH:52])[C:47]([F:50])([F:49])[F:48])[CH:41]=3)[N:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:34]3[C:33]4[C:28](=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=4)[NH:27][C:26]=3[N:25]=[C:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[N:51][O:52][S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:47]([F:50])([F:48])[F:49])[CH:41]=3)[N:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reaction time: 1 h
Yield: 113.6 %

Procedure:
Tosyl chloride (0.048 g, 0.251 mmol) was added portionwise to a cold mixture of methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.130 g, 0.229 mmol), 4-dimethylaminopyridine (2.79 mg, 0.023 mmol) and triethylamine (0.038 mL, 0.274 mmol) in DCM (10.00 mL) to give a white suspension. After one hour at room temperature, the amber solution was diluted with DCM (10 mL) and washed with water (3×10 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (188 mg, 99% yield) as a tan foam: MS m/z 723.2 (M+H)+; HPLC >89%, RT=2.09 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:24]=[N:23][C:22]4[N:21]5[CH2:25][CH2:26][CH2:27][CH2:28][C@H:20]5[C:19](=[O:29])[NH:18][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][C:15]4[CH:24]=[N:23][C:22]5[N:21]6[CH2:25][CH2:26][CH2:27][CH2:28][C@H:20]6[C:19](=[O:29])[NH:18][C:17]=5[CH:16]=4)[CH2:12][CH2:13]3)=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: O=C1Nc2cc(CN3CCN(c4ccc(Br)cc4)CC3)cnc2N2CCCC[C@@H]12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2ccc(N3CCN(Cc4cnc5c(c4)NC(=O)[C@@H]4CCCCN54)CC3)cc2)ccn1
Temperature: 135 °C

Procedure:
(S)-3-((4-(4-bromophenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (0.04 mmol), 2-methoxypyridin-4-ylboronic acid (0.060 mmol), PdCl2(dppf)-CH2Cl2 Adduct (3.27 mg, 4.00 μmol), sodium bicarbonate (0.500 ml, 0.500 mmol), dioxane (Volume: 1 ml) and a stir bar were sealed in a 5 mL microwave vial. The vial was heated to 135° C. for 30 minutes. The aqueous layer was removed from the vial and reaction mixture the filtered into a 1.8 mL HPLC submission vial. The reaction mixture was purified by LCMS to give a yellow solid: [M+H] calc'd for C28H32N6O2, 485; found, 485.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13]Br.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.NC1C=CC=CC=1>>[N+:10]([C:8]1[CH:9]=[C:4]2[C:5]([CH2:13][N:22]([C:21]3[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:3]2=[O:15])=[CH:6][CH:7]=1)([O-:12])=[O:11]
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: Nc1ccccc1
Product: COc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid methyl ester and 4-methoxyaniline instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-isoindol-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH3:24][CH:25]([CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:26][CH2:27][O:28][C:29](=[O:35])[CH2:30]CC(Cl)=O>C1COCC1.CCOCC>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH2:15][CH2:30][C:29]([O:28][CH2:27][CH2:26][CH:25]([CH3:24])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])=[O:35])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Reactant: CC(=O)OC=CC(C)c1cccc(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)OC=CC(C)c1cccc(C(C)C)c1
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution of 7.60 g acetic acid 3-(3-isopropyl-phenyl)-but-1-enyl ester in 50 ml of THF was cooled to −70° C. A solution of 5.00 g potassium-tert-butoxide in 50 ml of THF was added at 70° C. and the resulting reaction mixture was stirred for 2 hours at the same temperature. 11.20 g 3-chlorocarbonyl-propionic acid 3,7-dimethyl-oct-6-enyl ester was then dropped in and the reaction mixture was stirred for another 2 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was purified by chromatography to yield 7.10 g of a yellow oil.