Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23])([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])(=[O:24])=[O:23])([O-:12])=[O:11]
Reactant: Cc1occc(=O)c1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 28 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (1.58 g, 5.9 mmol) in 40 mL of pyridine to afford PZBG-2d in 28% yield (0.39 g, 1.1 mmol). 1H NMR (500 MHz, CDCl3) δ=8.72 (d, J=2.3 Hz, 1H), 8.56 (dd, J1=9.2 Hz, J2=2.3 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 7.71 (d, J=5.8 Hz, 1H), 6.31 (d, J=5.8 Hz, 1H), 2.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.6, 163.3, 154.9, 139.3, 136.4, 133.8, 126.8, 120.5, 117.5, 16.1. ESI-MS(+): m/z 357.03 [M+H]+, 378.99 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:39]=[CH:24][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:22]=3[CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (82 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (20 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (61 mg) and triethylamine (279 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 60) (86 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Temperature: 50 °C
Yield: 83.6 %

Procedure:
A solution of Intermediate 16 (0.21 g) in ethanol:water (95:5, 10 ml) was treated with sodium hydroxide (0.12 g). The mixture was heated at 50° C. for 8 h, then concentrated in vacuo, dissolved in water and acidified to pH 4 with acetic acid. The resultant white solid was removed by filtration and dried under vacuum to afford Intermediate 17 as an off-white solid (0.16 g). LCMS showed MH+=291; TRET=2.11 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)[O:5]CC)[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(OCC)C>[CH2:9]([P:4]([Cl:22])(=[O:5])[O:3][CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCP(=O)(OCC)OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCCCP(=O)(Cl)OCC
Temperature: -20 °C
Yield: 73 %

Procedure:
To a 500 mL round bottomed flask containing n-decylphosphonic acid diethyl ester, 22 g (79.0 mmol) was added to 100 mL of diethylether. This solution was stirred and cooled to −20° C. using an ice/salt water bath. Oxalyl Chloride (20.06 g, 158 mmol) was added in small portions over 45 minutes while maintaining the temperature at −20° C. The reaction mixture was then allowed to warm to room temperature and stirred for 24 hours. The solvent was removed by rotary evaporation to give a viscous liquid. The liquid was purified by vacuum distillation (boiling point: 126° C. at 0.4 mmHg) to give 15.5 g (73% yield) of the desired product. 1H NMR (400 MHz CDCl3): δ 4.2 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H), 1.2 (m, 17H), 0.75 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH2:14].[F:15][CH:16]([F:25])[C:17]([NH:19][C:20](=O)[O:21]CC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:20](=[O:21])[NH:19][C:17]([CH:16]([F:25])[F:15])=[N:14]1
Reactant: CCOC(=O)NC(=O)C(F)F
Reactant: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CC(C)Oc1cc(-n2nc(C(F)F)[nH]c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a stirred solution of 11.8 g (0.05 mole) of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine and 10.0 g (0.06 mole) of ethyl difluoroacetylcarbamate in 130 mL of xylene was added 2.5 g (0.02 mole) of phosphorus pentoxide. After complete addition the mixture was heated at reflux for 1.5 hours then allowed to cool to room temperature for approximately 18 hours. The reaction mixture was decanted from a dark residue in the reaction flask and washed with water. The washed mixture was extracted with a 10% aqueous sodium hydroxide solution. The basic extract was made acidic with concentrated hydrochloric acid to form an oily precipitate. This aqueous phase was decanted from the oily residue and fresh water added to wash the residue. This residue was dissolved in 160 mL of methylene chloride and filtered through a celite pad. The filtrate was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a semi-solid residue. The residue was triturated with approximately 125 mL of petroleum ether to provide 8.2 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH2:38])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]2)=[O:11])[CH2:5][CH2:4]1.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C1COCC1>CO>[F:41][C:2]([F:40])([F:1])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH:38][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C:30]=4[Cl:39])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([F:24])[CH2:22][CH2:23]2)=[O:11])[CH2:5][CH2:4]1
Reactant: NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reaction time: 0.33 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-5-fluoro-3-(aminomethyl)-phenylamino}-5-[4-fluoro-piperidinyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (130 mg, 0.210 mmol), pivaloyl chloride (26 μL, 0.21 mmol), TEA (75 mg, 0.74 mmol) and 5 mL THF is stirred for 20 min and diluted with MeOH. The crude product is purified via prep. HPLC (C-18 stable bond, eluent gradient: water(+0.15% HCOOH)/MeOH 9:1->MeOH).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Yield: 85.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example U-2, 0.19 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.18 g of the title compound as a solid, mp 231-233° C.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]([CH:35]([CH3:37])[CH3:36])([C:33]#[N:34])[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[CH:25]=3)[CH:20]=[N+:19]2[CH3:32])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]([CH:35]([CH3:37])[CH3:36])([C:33]#[N:34])[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[CH:25]=3)[CH2:20][N:19]2[CH3:32])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3C=[N+]2C)C(C)C)cc1OC
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC
Reaction time: 1 h

Procedure:
The resulting compound of formula 41 is then hydrogenated to produce a compound of formula 1. This hydrogenation is preferably performed using NaBH4. The solvent used is preferably a lower alkanol, particularly MeOH. The reaction is carried out at a temperature of about -10° C. to about 50° C., preferably about 0° C., over about 10 minutes to about 3 hours, preferably 1 hour. For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-3,4-dihydroisoquinolinium iodide (41) is suspended in MeOH at 0° C., then treated with NaBH4 for about 1 hour to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:20][NH2:21]>>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=3)[NH:21][N:20]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1F
Reactant: NN
Product: FC(F)(F)c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 2-fluoro-5-trifluoromethylbenzophenone (0.828 g, 3.09 mmol) in hydrazine was heated at 130° C. for 3 hours. The reaction mixture stood at ambient temperature overnight and gave white needles. It was filtered and washed with hexane to provide the title compound (0.617 g, 76% yield): mp 152° C.; 1H NMR (CDCl3) δ 10.63 (br s, 1H), 8.33 (s, 1H), 7.96 (d, 2H), 7.48-7.67 (m, 5H); EI-MS (m/z) 262 [M]+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:6]1[C:7](=[O:15])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:22]
Reactant: O=C(Cl)c1ccco1
Reactant: O=c1[nH]c2ccccc2c2ccccc12
Product: O=C(c1ccco1)n1c(=O)c2ccccc2c2ccccc21

Procedure:
5-(Furan-2-carbonyl)-5H-phenanthridin-6-one was prepared from 5H-phenanthridin-6-one and 2-furoyl chloride according to GP 1. Yield, 2%. 1H-NMR (CD3OD): δ=6.77 (dd, J=3.6 Hz, J=1.8 Hz, 1H), 7.44 (ddd, J=J=7.5 Hz, J=1.0 Hz, 1H), 7.41 (ddd, J=J=7.7 Hz, J=1.1 Hz, 1H), 7.48 (ddd, J=J=7.5 Hz, J=1.1 Hz, 1H), 7.54 (ddd, J=J=7.5 Hz, J=1.1 Hz, 1H), 7.57 (dd, J=3.6 Hz, J=0.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.95 (dd, J=1.8 Hz, J=0.7 Hz, 1H), 8.47 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=290 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[NH2:19])=[CH:6][CH:5]=1.[CH:21](O)=O>COC(OC)OC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[N:19]=[CH:21]2)=[CH:8][CH:9]=1
Reactant: O=CO
Reactant: COC(=O)c1ccc(CNc2ccc(C)cc2N)cc1
Solvent: COC(OC)OC
Product: COC(=O)c1ccc(Cn2cnc3cc(C)ccc32)cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
A stirred solution 4-[(4-methyl-2-nitrophenylamino)methyl]benzoic acid methyl ester (7.0 g, 23 mmol,) in CH3OH was treated with 5% Pd/C (50% wet, 30% w/w) and hydrazine hydrate (5.8 g, 116 mmol). The reaction mixture was heated to reflux temperature for 2 h, cooled to room temperature and filtered through celite. The filtrate was evaporated to give a residue. The residue was dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and evaporated to afford 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester, which was used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CDCl3) 8.0 (d, J=8 Hz, 2H); 7.70 (d, J=8 Hz, 2H); 6.60 (m, 2H); 6.49 (d, 1H); 4.3 (s, 2H); 3.90 (d, 3H); 2.21 (s, 3H). LCMS (ESI+) 271 (MH+). A stirred solution of crude 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester (6 g, 22 mmol) in trimethylorthoformate was treated with formic acid (1.0 g), refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The resultant residue was purified by column chromatography using 1% MeOH/CHCl3 to afford 4-[(5-methylbenzimidazol-1-yl)methyl]benzoic acid methyl ester Yield: 61%. 1H NMR (400 MHz, CDCl3): 8.0 (d, J=8 Hz, 1H); 7.93 (s, 1H); 7.62 (s, 1H); 7.26 (s, 1H); 7.21 (d, J=8 Hz, 2H); 7.08 (m, 2H); 5.39 (s, 2H); 3.90 (s, 3H); 2.47 (s, 3H). LCMS (ESI+) 281 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)cc1N
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(-c2cc(F)ccc2F)cc1N
Temperature: 95 °C

Procedure:
Bis(triphenylphosphine)palladium chloride (0.927 g, 1.321 mmol), 2-bromo-5-methylpyridin-4-amine (2.47 g, 13.21 mmol), Na2CO3 (6.60 mL, 13.21 mmol) and 2,5-difluorophenylboronic acid (2.71 g, 17.17 mmol) were combined and heated at 95° C. overnight. The reaction was cooled, filtered through a pad of Celite®, and concentrated directly onto silica gel and then purified by column chromatography (NH, silica) eluted with EtOAc/hexanes (0-100%) to give 2-(2,5-difluorophenyl)-5-methylpyridin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (3H, s) 5.96 (2H, s) 7.04 (1H, d, J=2.02 Hz) 7.20-7.29 (1H, m) 7.29-7.38 (1H, m) 7.68 (1H, ddd, J=9.73, 6.19, 3.28 Hz) 8.02 (1H, s). MS [M+H] found 221.2.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].Cl.[CH3:12][NH:13][O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([N:13]([O:14][CH3:15])[CH3:12])=[O:2]
Reactant: CNOC
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of phthalide (26.8 g) in methylene chloride (600 ml) were successively added N,O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) under ice-cooling, and triethylamine (139 ml) was added dropwise over 40 min. The mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into diluted hydrochloric acid, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-methylbenzamide. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was dissolved in N,N-dimethylformamide (300 ml), and imidazole (9.53 g) and tert-butyldimethylchlorosilane (21.1 g) were added. The mixture was stirred at room temperature for 3.5 hr and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (42.0 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1I
Yield: 63.6 %

Procedure:
A solution of 2-iodo-4-nitrophenol (2.2 g, 8.3 mmol), tert-butyl bromoacetate (1.6 mL, 11 mmol), and potassium carbonate (2.3 g, 17 mmol) in N,N-dimethylformamide (20 mL) was stirred at 20° C. for 60 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (2.0 g, 60%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:3].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=1.[H-].[Na+]>CCOCC.CCCCC>[F:24][C:18]1[CH:17]=[C:16]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[CH:4][N:2]([CH3:1])[CH3:3])[C:6]2=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Reactant: COc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(N2C(=O)C(=CN(C)C)c3ccccc32)cc1F

Procedure:
By the procedure of Example C1, without chromatography, but directly crystallizing the crude product from ether/pentane, 3-(dimethylaminomethylene)-2(1H,3H)-indolone (3.77 g, 20 mmoles) and 4-bromo-2-fluoroanisole (4.10 g, 20 mmoles) with NaH (0.96 g of 50% dispersion in oil, 20 mmoles) and Cu2Br2 (5.74 g, 20 mmoles), were converted to title product, 0.79 g, m.p. 113°-114°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:29]=[CH:30][N:31]=2)[CH:5]=[C:6]([C:17]([N:19]2[CH2:22][C:21]([CH:24]([N+:26]([O-])=O)[CH3:25])([OH:23])[CH2:20]2)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:26][CH:24]([C:21]1([OH:23])[CH2:22][N:19]([C:17]([C:6]2[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:2]([Cl:1])[C:3]3[N:4]([CH:29]=[CH:30][N:31]=3)[CH:5]=2)=[O:18])[CH2:20]1)[CH3:25]
Reactant: CC([N+](=O)[O-])C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol (195 mg 0.35 mmol) in tetrahydrofuran/water (5 mL, 4:1) was added iron powder (193 mg, 3.5 mmol) and ammonium formate (438 mg, 7.0 mmol). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature and filtered through a pad of celite. The celite was washed three times with boiling ethanol (20 mL). The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The precipitate which formed was filtered through a pad a celite and the filtrate was partitioned with water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow residue which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford mg, 0.05 mmol (15%) of 3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol acetate salt as a white solid. 1H NMR (400 MHz, DMSO): 8.79 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.54-6.48 (m, 1H), 4.24-4.13 (m, 1H), 3.98-3.84 (m, 2H), 3.61-3.56 (m, 1H), 2.83 (q, 1H), 0.92-0.88 (m, 3H); MS (EI) for C19H18ClFIN5O2: 530 (MH+).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1>CN(C)C=O>[NH2:14][C:13]1[CH:12]=[C:11]([CH2:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([NH:7][C:27]3[C:28]([Cl:32])=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=3)[CH:8]=[CH:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(CCCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(CCCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Reaction time: 2.5 h
Yield: 33.1 %

Procedure:
To a solution of 3,3′-propane-1,3-diyldianiline (41.0 mg, 0.181 mmol) in N,N-dimethylformamide (1.0 mL), potassium carbonate (72 mg, 0.52 mmol) was added followed by 2,4,5-trichloropyrimidine (20 μL, 0.17 mmol). The mixture was stirred for 2.5 hours and purified by preparative LCMS (pH 10) to give the desired product (21 mg, 32%). LCMS for C19H19Cl2N4 (M+H)+: m/z=373.1.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([N+:25]([O-:27])=[O:26])=[CH:11][CH:10]=1>CO.C(Cl)Cl>[CH3:1][O:16][C:15](=[O:17])[C:14]1[C:9]([F:8])=[CH:10][CH:11]=[C:12]([N+:25]([O-:27])=[O:26])[C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
Trimethylsilyldiazomethane (2M in hexane, 7.24 mL, 14.5 mmol) was added dropwise to a solution of 6-fluoro-3-nitro-2-phenylaminobenzoic acid (2.0 g, 7.24 mmol) in MeOH (5 mL) and DCM (40 mL) at RT. The solution was stirred at RT for 45 min then the volatiles were removed under reduced pressure to afford the title compound (2.1 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 9.67 (1H, br s), 8.32 (1H, dd, J=9.47, 5.75 Hz), 7.36-7.30 (2H, m), 7.23-7.07 (3H, m), 6.64 (1H, dd, J=9.47, 8.33 Hz), 3.27 (3H, s)