Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nccnc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-aminopyrazine-3-carboxylate (5.0 g, 32.65 mmol) was dissolved in 100 mL of THF and treated with N-Bromosuccinimide (6.9 g, 39.18 mmol) all at once. The mixture was stirred at room temperature for 1.5 hrs, and then another 0.5 equivalents of N-bromosuccinimide was added and stirring continued for 1 hr. 10 grams of sodium sulfate were added, the mixture was vigorously stirred for 15 minutes, and the solvent was removed in vacuo. The residue obtained was suspended in 250 mL of water and stirred rapidly. Filtration afforded the title compound, methyl 3-amino-6-bromopyrazine-2-carboxylate, as a tan solid (6.33 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:14][C:16](=[O:18])[CH3:17])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a 1 L 3-necked round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged 150 g (0.70 mol) of (4R,5R)-3-amino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester and 50 mL of dry CH2Cl2. The reaction mixture was cooled to −20° C. To the mixture was added, successively, acetyl chloride (60 mL, 0.84 mol) and pyridine (66.8 g, 0.84 mol) over 0.5-hour time intervals. After the additions, the mixture was stirred at −20° C. to 0° C. for 2 hours and then filtered to remove the pyridine.HCl salt. The filtrate was diluted with 200 mL of CH2Cl2 and washed 2× with aliquots of aq NH4Cl. The organic solution was treated with silica gel (50 g), MgSO4 (20 g) and charcoal (20 g), and stirred at room temperature for 0.5 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 166.5 g (93% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.85 (t, J=7.4 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 1.00 (d, J=7.0 Hz, 3H), 1.11 (m, 1H) 1.29 (t, J=5.8 Hz, 3H), 1.40-1.25 (m, 2H), 1.65 (m, 1H) 2.13 (s, 3H), 3.80 (m, 1H) 4.2-4.14 (m, 3H), 5.01 (s, 1H), 11.28 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]2[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:26])[N:11]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][N:11]2[C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]=3[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12]2=[O:26])=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 3,8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the method of Example 4, 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:4]2[CH2:3][C:2]([CH3:20])([CH3:1])[O:7][CH2:6][C:5]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:23]=1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)OC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)C1=C(c2ccc(Cl)cc2)CC(C)(C)OC1

Procedure:
To a solution of EXAMPLE 38B (2.88 g), 4-chlorophenylboronic acid (1.88 g) and tetrakis(triphenylphosphine)palladium(0) (0.578 g) in toluene (40 mL) and ethanol (10 mL) was added 2N aqueous Na2CO3 (10 mL). The mixture was stirred at reflux overnight. The mixture was diluted with ether (300 mL) and washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a column and eluted with 3% ethyl acetate in hexane to give the product.
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[NH:18][C:17](=[O:26])[C@@H:16]2[CH2:27][CH3:28])(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>CS(C)=O>[CH2:31]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)(=[O:13])=[O:14])[C@@H:16]([CH2:27][CH3:28])[C:17]1=[O:26])[CH3:32]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(C)ccc3NC(=O)[C@@H]2CC)cc1
Reactant: CCI
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Solvent: CS(C)=O
Product: CC[C@H]1C(=O)N(CC)c2ccc(C)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
Ethyl 4-{[(2S)-2-ethyl-7-methyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-6-methyl-3,4-dihydroquinoxalin-2(1H)-one [α]D25=−118° (c=0.0054 G/ML, DMSO); MS (ESI) m/z 375 ([M+H]+); MS (ESI) m/z 373 ([M−H]−); Anal. Calcd for C19H22N2O4S: C, 60.94; H, 5.92; N, 7.48. Found: C, 61.50; H, 5.99; N, 6.89.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH:22]1[C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]=2[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:18][CH:17]=2)=[CH:20][CH:21]=1
Reactant: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4-formylphenylboronic acid (0.9 g, 5.64 mmol) in ethanol (10 mL) was added to a stirred solution of the crude 4-(4-bromophenyl)-dibenzofuran (from the previous reaction) in toluene (40 mL). tetrakis-(Triphenylphosphine)palladium(0) (270 mg, 5 mol %) and 2N sodium carbonate (4.7 mL, 9.4 mmol) were added and the reaction was heated to 100° C. (oil bath temp.) for 2-3 hrs until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated, the aqueous phase being further extracted with ethyl acetate (2×20 mL). The combined extract was washed with 0.5 N hydrochloric acid, water and brine and then dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 10-20% ethyl acetate in hexane as eluent, afforded the title compound has a white solid (1.51 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[OH-:22].[Na+].[Cl-:24].[NH4+]>CN(C)C=O>[Cl:24][C:5]1[O:22][C:13]([CH2:12][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccc(Cl)o2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 70 °C
Yield: 62 %

Procedure:
To an ice-cooled solution of (5-chloro-2-furyl)methanol (2.03 g, 15.3 mmol) in anhydrous dichloromethane (50.0 mL) was added triethylamine (4.64 g, 45.9 mmol) followed by thionyl chloride (3.64 g, 30.6 mmol). The reaction mixture was stirred at 0° C. for 30 min and quenched with saturated ammonium chloride (25.0 mL). After the aqueous layer was separated, the organic layer was washed with 10% aqueous HCl (20.0 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to drynessto give 5-chloro-2-chloromethylfuran as a yellow oil. A solution of this oil in anhydrous N,N-dimethylformamide (3.00 mL) was added directly without any further purification to a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.84 g, 3.00 mmol) and sodium hydroxide (0.48 g, 12.0 mmol) in anhydrous N,N-dimethylformamide (9.00 mL). The reaction mixture was heated at 70° C. for 16 h, cooled to ambient temperature followed by the addition of saturated ammonium chloride (5.0). N,N-Dimethylformamide was removed under high vacuum. The residue was diluted with ethyl acetate (100 mL), washed with 10% aqueous HCl (25.0 mL), brine (25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The brown residue was subjected to column chromatography eluting with ethyl acetate/hexane (35%) to afford the title compound (0.74 g, 62%) as a colorless solid: mp 148-150° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.29 (t, 1H), 7.15-7.12 (m, 2H), 7.01 (d, 1H), 6.67 (s, 1H), 6.60 (d, 1H), 6.39 (d, 1H), 6.10 (s, 1H), 5.89 (d, 2H), 4.89 (ABq, 2H), 4.72 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.9 155.8 149.7, 148.8, 142.2, 142.1, 134.8, 132.1, 129.3 124.1, 123.7 120.2, 112.0, 109.9, 108.2 103.2, 101.9, 93.8, 80.0, 57.9 37.0; MS (ES+) m/z 396 (M+1).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])(=O)=O.O>CN(C)C=O>[F:23][C:19]([F:24])([CH:20]([F:22])[F:21])[CH2:18][C:2]([CH2:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CC(F)(F)C(F)F)CC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
7.5 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide and 10.4 g of potassium carbonate was added. The mixture was stirred at room temperature for 1 hour, 10.0 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate dissolved in 20 ml of N,N-dimethylformamide was added dropwise, and the mixture was stirred overnight. Thereafter, the reaction mixture was poured to water and extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The resulting fraction was washed with chloroform to obtain 0.08 g of 2,2-bis(2,2,3,3-tetrafluoropropyl)malononitrile (hereinafter, referred to as the present compound (50)).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:22])[N:6]=1)[CH2:3][CH3:4].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH3:22][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13](=[O:21])[N:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([CH:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH2:3][CH3:4])=[N:6]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: CCC(N)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Compound 17 (100 mg, 0.341 mmol) was combined with 6-bromo purine (75 mg, 0.375 mmol) and diisopropylethylamine (65 uL, 0.375 mmol) inn-butanol (1.0 mL). The reaction was sealed, heated to 120° C., and stirred for 18 hours. The solution was allowed to cool, then concentrated in vacuo. The resulting residue was purified by prep HPLC to provide compound 14 as an olive solid. (ES): m/z 412 (M+H), 206. 1H NMR (300 MHz, DMSO-d6) δ 8.96-9.06 (br. m, 1H), 8.53 (br. s, 1H), 8.51 (s, 1H), 7.68 (t, 1H, J=7.8 Hz), 7.45-7.62 (m, 6H), 7.31 (d, 1H, J=7.3 Hz), 4.76-4.86 (m, 1H), 2.73 (s, 3H), 1.98-2.11 (m, 1H), 1.76-1.94 (m, 1H), 0.79 (t, 3H, J=7.2 Hz). The reaction described above and compound 14 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:26][N:27]([CH3:35])[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[CH:7][C:3]=1[C:4]([C:29](=[CH:28][N:27]([CH3:35])[CH3:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:6]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: 90 °C
Yield: 23.3 %

Procedure:
95 mg (0.27 mmol) of 2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)benzoic acid were boiled with 0.98 ml of thionyl chloride under reflux for 3 hours. The thionyl chloride was distilled off, and the residue was mixed with 3 ml of toluene and concentrated in vacuo. The residue was taken up in 2 ml of toluene and added to a solution of 39 mg (0.27 mmol) of ethyl 3-dimethylaminoacrylate, 6 μl of triethylamine and 1 ml of toluene. The mixture was heated at 90° C. for 3 hours. The mixture was concentrated and chromatographed on silica gel (heptane:ethyl acetate=75:25 to 0:100 in 45 minutes). 30 mg (23%) of the desired product were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 0.087 mol) in 150 ml 1,2-dimethoxyethane is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 0.096 mol) and tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.00174 mol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with 200 ml of ethyl acetate. The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1.C1COCC1.O.[OH-].[Li+].Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CNC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CNC2=O
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 100 mL round bottom flask containing methyl 1-oxoisoindoline-5-carboxylate (200 mg, 1.046 mmol) was added THF (6 mL) and H2O (2 mL) the mixture was stirred at 23° C. for 2 min. At this time, lithium hydroxide monohydrate (87 μL, 3.14 mmol) was added and the flask was gently heated on aluminum block for 5 min. The solid went into solution and LC/MS showed product formation. The contents of the reaction were poured into HCl (1 M, 15 mL) and extracted with DCM (15 mL). An emulsion formed, the layers separated, and a white solid formed at the boundary of the layers and stuck to the separatory funnel. This material was collected, dissolved in MeOH, and concentrated. After drying under high vacuum for 2 h, the 1-oxoisoindoline-5-carboxylic acid thus obtained was taken on directly to the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OC1CCOCC1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C1CCOCC1

Procedure:
Compound IIe was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and tetrahydro-2H-pyran-4-ol following the general procedure for the Mitsunobu reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C=O.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][C:17]=1[CH3:25].[C:26](=O)([O-])[O-].[K+].[K+]>C(O)C>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:22][CH2:26][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[O:21])=[CH:18][C:17]=1[CH3:25]
Reactant: Cc1cc(C(N)=O)ccc1F
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C(=O)NCN2CCN(c3ccccn3)CC2)ccc1F
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 4-fluoro-3-methylbenzamide (77 mg, 0.5 mmol, Oakwood), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 25 mg (51%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.58 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.18 (d, J=5 Hz, 1H), 6.61 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.21 (t, J=6 Hz, 1H), 7.51 (t, J=5 Hz, 1H), 7.75 (t, J=5 Hz, 1H), 7.82 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.76 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 327 (M−H)+.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([Cl:23])=[CH:16][C:15]=1[O:24][CH3:25].P(OCC)(OCC)OCC.O>CN(C)C=O>[CH3:25][O:24][C:15]1[CH:16]=[C:17]([Cl:23])[C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[C:3]1[NH:2][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)n1O
Agent: CCOP(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)[nH]1
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 1-hydroxy-2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (9.7 g) and triethyl phosphite (8.9 g) in N,N-dimethylformamide (100 ml) was stirred at 80°-90° C. for one hour. The reaction mixture was poured into water and the resultant mixture was stirred at ambient temperature for one hour. The precipitate was collected by filtration and washed with water and ethyl acetate and dried to give 2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (7.6 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH2:9][OH:10])=O.C(N(CC)CC)C>CO>[NH2:4][C:3]1[O:10][CH:9]=[C:7]([CH3:6])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: CC(=O)CO
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1coc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a mixture of malononitrile (0.96 g, 14.6 mmol), acetol (1.08 g, 14.6 mmol) in methanol (10 mL) at 0° C. was added, dropwise, triethylamine (2.0 mL). The reaction mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure the crude solid washed with cold isopropanol to give product as white powder (0.54 g, 30%). HPLC/MS: (M+H)+ 123.3 m/z. Retention time (LC-MS)=1.81 min. 1H NMR (CD3OD): 6.58(s, 1H,); 1.95 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[NH2:20][C:21]1[O:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=1>>[CH3:29][O:28][C:26]([C:23]1[O:22][C:21]([NH:20][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:25][CH:24]=1)=[O:27]
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: COC(=O)c1ccc(N)o1
Product: COC(=O)c1ccc(NC(=O)c2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)o1
Yield: 10 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-amino-5-methoxycarbonylfuran, 1.3 mg (10%) of the title compound were recovered.