Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:18]=2)[C:13]([Cl:28])=[CH:12][N:11]=1>CN1C(=O)CCC1>[Cl:28][C:13]1[C:14]2[C:19](=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[N:11][CH:12]=1
Reactant: N=C(N)N
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: O=C(O)O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 84848.5 %

Procedure:
A stirred suspension of guanidine carbonate (720 g, 4.0 mol) in NMP (5 L) was heated to 130° C. under N2 for 1 hour. The suspension was cooled to room temperature and 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (1.0 kg, 3.3 mmol) was added as a solid. The mixture was heated at 130° C. for 4 hours, cooled to room temperature, filtered through a pad of clarcel. Water (6.7 L) was added to the filtrate. The resultant slurry was cooled to 5° C., stirred for 1 hour and the solid collected by filtration. The solid was washed with a mixture of NMP:water (1:1, 4 L) and water (4 L) and dried in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (900 g, 2.8 mol, 85%) as a green solid.
Reaction SMILES: I[Si](C)(C)C.[C:6]([C:11]1[C:12](=[O:30])[CH2:13][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][O:27]C)[C:19]=2[CH3:29])[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:7][CH2:8][CH3:9]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[C:6]([C:11]1[C:16](=[O:17])[CH2:15][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][OH:27])[C:19]=2[CH3:29])[CH2:13][C:12]=1[OH:30])(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(COC)c2C)CC1=O
Agent: [Ag+]
Agent: C[Si](C)(C)I
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CO)c2C)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Iodotrimethylsilane (0.3 ml) was added to a solution of 2-butyryl-3-hydroxy-5-(3-methoxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.5 g, 1.45 mmole) (see Example 36) in dry acetonitrile (10 ml) under nitrogen and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of silver nitrate was added and the mixture was stirred for a further 4 hours. The solvent was evaporated and the residue was washed successively with dilute aqueous sodium hydroxide and acetic acid, then dissolved in ethyl acetate and dried over anhydrous sodium sulfate. Evaporation under reduced pressure yielded 2-butyryl-3-hydroxy-5-(3-hydroxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.42 g; 87.0%) as an oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:34]([CH:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35]>O1CCCC1>[C:37]1([CH:36]([NH:43][C:16]([C:12]2[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:14][C:13]=2[CH3:15])=[O:18])[CH2:34][CH3:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCC(N)c1ccccc1
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCC(NC(=O)c1sc(NC(=O)c2ccccc2)nc1C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 2-benzoylamino-4-methylthiazole-5-carboxylic acid (0.13 g, 0.50 mmol) and 4-methylmorpholine (0.08 mL, 0.70 mmol) in tetrahydrofuran (20 mL) at 0° C. was added iso-butylchloroformate (0.08 mL, 0.60 mmol). The reaction mixture was stirred for 15 minutes, then warmed to ambient temperature and stirred for another hour before α-ethylbenzylamine (0.1 mL, 0.70 mmol) was added. The reaction mixture was kept stirring at ambient temperature overnight and then concentrated. Purification of the residue by column chromatography afforded the title compound in 19% yield (0.037 g); m. p. 87-89° C.; 1H NMR (CDCl3, 300 MHz) δ 7.89-7.86 (m, 2H), 7.61-7.22 (m, 8H), 5.91 (d, J=7.5 Hz, 1H), 5.02-4.94 (m, 1H), 2.33 (s, 3H), 2.27-1.78 (m, 2H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.1, 161.4, 157.0, 152.1, 141.8, 133.3, 131.4, 129.1, 128.7, 127.6, 127.5, 126.6, 118.8, 55.6, 29.3, 16.7, 10.8. MS (ES+) m/z 380.5 (M+1).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16]>C(OC)(C)(C)C>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13]
Reactant: CC[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: COC(C)(C)C
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 130 ml of a t-butyl methyl ether (chain ether solvent) solution containing 0.198 mol of suspended ethyl magnesium bromide as the hydrocarbon magnesium halide (2) was charged to the reaction vessel. Meanwhile, 0.182 mol of bromopentafluorobenzene was charged to the dropping funnel. Then, bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 45 minutes at room temperature, and the reaction solution was stirred for 4 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless t-butylmethyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 98.0 mol % based on bromopentafluorobenzene.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reactant: C1COC(CN2CCNCC2)C1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CCCO3)CC2)cc1
Yield: 12 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 12%. White crystals, m.p. 220–221° C.; IR (KBr): ν 1708 (ester C═O), 1660(amide C═O) cm−1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:17])[CH2:10][N:11]=[C:12](SC)[S:13][CH3:14].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O1CCCC1.O>[CH3:7][O:8][C:9]([C:10]1[N:11]=[C:12]([S:13][CH3:14])[O:24][C:23]=1[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)CN=C(SC)SC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(SC)oc1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 16.4 %

Procedure:
A suspension of potassium tert-butoxide (1.18 g; 10.52 mmol) in dry tetrahydrofuran (20 ml), cooled at -78 C., under argon, is treated with a solution of N-[bis(methylthio)methylene] glycine methyl ester (1.02 g; 5.26 mmol) in dry tetrahydrofuran (7 ml). After stirring for 45 minutes, it is added a solution of 4-fluorobenzoyl chloride (0.75 g; 6.31 mmol) in tetrahydrofuran (7 ml). After stirring at -78 C. for 20 minutes, it is brought to room temperature and stirred an additional 16 hours. The reaction mixture is diluted with water (30 ml) and extracted with ethyl acetate (70 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (20 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%) affords the product as a white solid (0.23 g; 16%). HNMR (CDCl3): 8.07 (m, 2H), 7.16 (t, 2H, J=8.9 Hz), 3.93 (s, 3H), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=268.3; observed (MH+)=268.1.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[Cl:9][C:10]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:11]=1[CH:12]=O>CO>[NH2:1][C:2]([C:7]#[N:8])=[C:3]([N:6]=[CH:12][C:11]1[C:14]([Cl:22])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:10]=1[Cl:9])[C:4]#[N:5]
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CO
Product: N#CC(N)=C(C#N)N=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
Diaminomaleonitrile (4.4 g, 0.04 mol) was dissolved in methanol (100 ml) and 2,6-dichloro-4-trifluoromethylbenzaldehyde (9.6 g, 0.04 mol) was added with stirring at ambient temperature. The reaction mixture was stirred for 30 minutes and heated at reflux for 1 hour. After cooling to 10° C. a solid which had separated was filtered off to give 1-amino-2-(2,6-dichloro-4-trifluoromethylbenzylideneamino)- 1,2-dicyanoethylene (10.3 g) as a yellow crystalline solid, m.p. 218°-219° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=Cc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(C=O)cc3)c3nc[nH]c3n2)CC1

Procedure:
300 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 288 mg of the product obtained in stage 1 above are added. 35 mg of the expected product are thus obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][C:5]=1[N+]([O-])=O)[CH3:2].BrCC(Cl)=[O:17]>C(Cl)(Cl)Cl>[C:1]([NH:3][C:4]1[CH:10]=[CH:9][CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:2]
Reactant: CCNc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)CBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
To a 100 mL flask was added 4-ethylamino-3-nitroaniline (1.1 g, 6.3 mmol) and anhydrous CHCl3 (45 mL). The solution was cooled to 0° C. prior to the addition of bromoacetyl chloride (0.62 mL, 7.5 mmol) and TEA (1.7 mL, 13 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over 1 h before the solvent was removed under reduced pressure. The crude material was chromatographed (SiO2, 0-40% EtOAc/Hex) to provide the intermediate acetanilide (540 mg, 1.8 mmol) as a red solid. To a solution of the intermediate in anhydrous DMF (25 mL) was added sodium acetate (1.41 g, 17.2 mmol). The suspension was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with EtOAc (25 mL), and the excess sodium acetate was removed by filtration under reduced pressure. The filtrate was concentrated under reduced pressure to provide the title compound (420 mg). 1H-NMR (CDCl3): δ 8.13 (1H, br s), 8.11 (1H, d), 7.90 (1H, br s), 7.79 (1H, dd), 6.80 (1H, d), 4.68 (2H, s), 3.33 (2H, m), 2.21 (3H, s), 1.35 (3H, t); MS(ESI): 282 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][S:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][S:11][C:10]4[CH:19]=[CH:20][CH:21]=[CH:22][C:9]3=4)=[O:6])[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=C(CCCCl)NC1c2ccccc2CSc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(F)cc2)CC1)NC1c2ccccc2CSc2ccccc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69.8 %

Procedure:
A mixture of 5.0 g of 11-(4-chlorobutyrylamino)-6,11-dihydrodibenzo[b,e]thiepin, 5.5 g of 1-(4-fluorophenyl)piperazine, 5.0 g of sodium iodide and 50 ml of dimethylformamide is stirred at 100° C. for 1.5 hours. After the reaction mixture is cooled to room temperature, 100 ml of 10% aqueous potassium carbonate solution is added and the solution is extracted with three 300-ml portions of chloroform. The combined extracts are washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and the chloroform is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (100:3) to give 5.0 g of the title compound. m.p. 194°-194.5° C. (recrystallized from chloroform-n-hexane);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:25]4[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH3:19])=[CH:23][CH:24]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)cc1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 4-fluoroacetophenone (51 μL, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (79 mg, 53%) as an off white solid. MS: m/e=362.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[F:38][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[CH:34][C:29]=1[C:27]#[N:28]
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc(C#N)c(F)c3)nn3ccnc23)cc1
Temperature: 100 °C
Yield: 24.4 %

Procedure:
To a vial was added 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine (100 mg, 0.274 mmol) from Example XXXVI(1) step (1a), 4-cyano-3-fluorophenylboronic acid (49.7 mg, 0.302 mmol), tetrakis(triphenylphosphine) palladium (17.4 mg, 0.015 mmol) and cesium carbonate (295 mg, 0.905 mmol in water (0.2 mL)) and DMF (2 mL). The solution was heated to 100° C. for 10 hours. The crude product mixture was filtered through celite, concentrated in vacuo and purified by preparative HPLC to give 2-fluoro-4-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile (30 mg, 24%). LC/MS, m/e 463 (M+1). HPLC Rt, 3.80 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[CH3:27]I.O>CN(C=O)C>[CH3:27][O:19][C:18]([C:15]1[C:16]2[O:17][C:6]3[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=[C:2]([CH3:1])[C:7]=3[C:8](=[O:9])[O:10][C:11]=2[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:20]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Temperature: 25 °C

Procedure:
Psoromic acid (1 mmol) was dissolved in DMF (10 mL), KHCO3 (2.4 mmol) was added and stirred for several minutes at room temperature. Then, CH3I (1.2 mmol) was added. The reaction mixture was maintained at 40° C. and monitored by TLC. Upon completion, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate. The organic layer was subsequently washed with saturated NaHCO3 solution and saturated brine, and dried over anhydrous MgSO4, filtered and evaporated by a rotatory evaporator. The residue was purified by column chromatography to provide a white solid product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]>>[CH3:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([O:10][CH3:9])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1cc(Cl)ncn1
Product: COc1cc(-c2cc(C)ncn2)cc(OC)c1OC

Procedure:
4-Chloro-6-methylpyrimidine (913 mg) and 3,4,5-trimethoxyphenylboronic acid (2.73 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC(N(C)C)=O.O>[CH3:17][C:12]1[CH:11]=[CH:10][C:15]([O:16][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccccc2C=O)cc1
Temperature: 150 °C
Yield: 50.4 %

Procedure:
To a solution of 2-fluorobenzaldehyde (3.54 g, 28.5 mmol) in DMA (20 mL) is added p-cresol (3.08 g, 28.5 mmol) and K2CO3 (4.72 g, 34.2 mmol), and the reaction mixture is heated to 150° C. for 12 h. Once complete, the reaction mixture is cooled to room temperature and diluted with water (100 mL) prior to being poured into a separatory funnel containing ethyl acetate (250 mL). The organic layer is separated, washed with brine (2×) and dried over sodium sulfate prior to concentration. The crude product is purified by column chromatography (5% ethyl acetate in hexanes) to afford 2-(4-methylphenoxy)-benzaldehyde (3.05 g, 50%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:19]#[N:20])=[N:14][CH:15]=[C:16](Cl)[CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>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(OCC)(=O)C.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:17]=[C:12]([Cl:11])[C:13]([C:19]#[N:20])=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Temperature: 45 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a 100 mL round bottom flask adapted for magnetic stirring and equipped with a nitrogen inlet was charged (3-chlorophenyl)boronic acid (5 g, 32 mmol), 3,5-dichloro-2-cyanopyridine (5.8 g, 34 mmol), K2CO3 (5.5 g, 40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5 mL). The reaction solution was agitated and heated to 45° C. and held at that temperature for 18 hours after which the reaction was determined to be complete due to the disappearance of 3,5-dichloro-2-cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase was isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase was dried for 4 hours over MgSO4, the MgSO4 removed by filtration and the solvent removed under reduced pressure. The residue that remained was then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid was collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford 5.8 g (73% yield) of an admixture containing a 96:4 ratio of the desired regioisomer. 1H NMR (DMSO-d6) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1Cl
Yield: 73.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), morpholine (150 mg, 1.72 mmol) and triethylamine(479 μL, 3.44 mmol) were reacted to form the desired product (430 mg, 73%). LC-MS (m/z) 341.0 (M−).
Reaction SMILES: [C:1]1([C:7]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:1]1([C:7](=[N:8][O:9][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ON=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone oxime (Example 39) (100 mg, 0.42 mmol) and sodium hydride (17 mg of a 60% in mineral oil, 0.43 mmol) in N,N-dimethylformamide (4 mL) was stirred for 0.5 h. tert-Butyl bromoacetate (60 μL, 0.41 mmol) was added dropwise and the reaction mixture was heated at 60° C. for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with diethyl ether (3×15 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over sodium sulfate and concentrated to an oil. Purification by Biotage chromatography (1-10% methanol in methylene chloride) provided tert-butyl [[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]acetate as a tan solid: mp 47-52° C.; 1H NMR (500 MHz, CDCl3) δ 1.46-1.61 (9H, m), 4.63 (0.66H, s), 4.85 (1.33H, s), 6.37 (0.33H, s), 6.53 (0.66H, s), 7.26-7.62 (6H, m), 8.23-8.28 (0.66H, m), 8.84 (0.33H, br s), 8.96 (1H, br s), 9.13 (0.33H, br s), 11.04 (0.66H, br s); ESI MS m/z 352 [C20H21N3O3+H]+; HPLC (Method A) 97.8% (AUC), tR=18.3 and 18.5 min.