Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1cccs1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccs1
Yield: 89 %

Procedure:
The compound prepared in Example 3 was reacted with thiophen-2-ylmethyl-amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 89%).
Reaction SMILES: CC1C=CC=CC=1C.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:31]([F:34])([F:32])[F:33])[CH:23]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-xylene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.8 g (0.01 mole) of 4-chloro-3-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 10 hours under reflux (140°-145° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-xylene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 3. m.p. 156°-158° C., yield 2.3 g (55%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4c(c3)C(=O)c3ccccc3-4)c2cc1OC
Temperature: 160 °C
Reaction time: 7 h
Yield: 33.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-9-fluorenone (269 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (58 mg, yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][N:17]2[C:18](=[O:27])[C:19]3[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.9 g) in dry acetonitrile (50 ml) was added N-(2-bromoethyl)phthalimide (3.6 g) followed by milled potassium carbonate (3.8 g) and potassium iodide (catalytic amount) at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 18.5 hrs, cooled to ambient temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was diluted with ether and methanol, the mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane). The appropriate fractions were collected and concentrated to afford a total 2.1 g (54%) of product. Recrystallization from ether gave the analytical sample, mp 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](C(F)(F)F)=[CH:18][CH:17]=2)=[CH:12][N:11]=1)=[O:8])=[O:5].NC1C=NC(C2C=CC(C(F)(F)F)=CC=2)=CN=1.[Cl:47]C1C=CC=CC=1C(N=C=O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:47])=[CH:18][CH:17]=2)=[CH:12][N:11]=1)=[O:8])=[O:5]
Reactant: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=C=NC(=O)c1ccccc1Cl
Agent: Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(Cl)cc2)cn1

Procedure:
2M. 1-(2-Chlorobenzoyl)-3-[5-(α,α,α-trifluoro-p-tolyl)-2-pyrazinyl]urea, having a melting point of about 213°-215° C., and weighing 0.6 g., from 0.6 g. of 2-amino-5-(α,α,α-trifluoro-p-tolyl)pyrazine and 0.55 g. of 2-chlorobenzoyl isocyanate.
Reaction SMILES: COC(=O)CCCCCCC(NC1SC=C(C2C=CC=C([N+]([O-])=O)C=2)N=1)=O.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)([O-:30])=[O:29].[CH2:43]([O:50][NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])=[O:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:39]([NH:42][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][C:52]([NH:51][O:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:53])[S:40][CH:41]=1)([O-:30])=[O:29]
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Reactant: O=C(O)CCCCCCC(=O)NOCc1ccccc1
Agent: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Product: O=C(CCCCCCC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1)NOCc1ccccc1

Procedure:
Compound 15 was prepared using the methodology described for the preparation of compound 14, by substituting 4-(3-nitrophenyl)-thiazol-2-ylamine with 4-(2-nitrophenyl)-2-thiazolamine (12) and using of compound 5 instead of compound 13. 1H NMR (400 MHz, DMSO-d6) δ (ppm). 12.14 (1H, s), 10.93 (1H, s); 7:88 (1H; d, J=7.4 Hz), 7.77 (1H, t, J=7.0 Hz), 7.72 (1H, d, J=7.4 Hz), 7.60 (1H, t, J=7.0 Hz), 7.51 (1H, s), 7.38-7.33 (5H, m), 4.78 (2H, s), 2.44 (2H, t, J=7.3 Hz), 1.94 (2H, t, J=7.3), 1.58 (2H, m), 1.49 (2H, m), 1.30-1.18 (4H, m).
Reaction SMILES: CO.[CH3:3][NH:4][CH3:5].[C:6]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)#[N:7]>>[NH2:7][CH2:6][C:8]1[CH:9]=[C:10]([S:14]([N:4]([CH3:5])[CH3:3])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a 2M dimethylamine methanol solution (3.7 ml) was added 3-cyanobenzenesulfonyl chloride (1.5 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. 10% Palladium carbon powder (0.79 g) was added to a solution (10 ml) of the residue in ethanol, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give 3-(aminomethyl)-N,N-dimethylbenzenesulfonamide (1.0 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:11]([CH2:10][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C(C)C

Procedure:
Using General Procedure A: Reaction of (3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 5-Cyano-2-{[(3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1C[CH2:21][CH2:20][CH2:19]1.C(Cl)(=O)C=C>CC(C)=O>[C:19]([O:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[CH:20]=[CH2:21]
Reactant: C1CCOC1
Reactant: OCCSc1ccccc1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)OCCSc1ccccc1
Temperature: -30 °C
Yield: 62 %

Procedure:
To a 500 mL three-neck round bottom flask equipped with mechanical stirrer were charged 2-hydroxyethyl phenyl sulfide (33.0 g, 0.21 mol), anhydrous triethylamine (45 mL, 0.32 mol), and anhydrous tetrahydrofuran (160 mL). The solution was cooled in a −30° C. acetone/dry ice bath under nitrogen blanket for 15 mins. Acryloyl chloride (22 mL, 0.27 mol) was added into the vigorously stirred cold solution through an addition funnel over 30 min. After the addition, the reaction mixture was stirred in the cold acetone bath for additional four hours followed by quenching with the addition of 2M HCl (200 mL). The mixture was extracted with diether ether (150 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as a light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (50/1, v/v) as eluent to give the final product as a colorless oil (27.4 g, 0.13 mol, yield: 62%), H1 NMR (CDCl3): δ 7.44 (2H), 7.33 (2H), 7.24 (1H), 6.41 (1H), 6.12 (1H), 5.85 (1H), 4.35 (2H), 3.21 (2H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O([C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[C:32]([F:33])=[CH:31][C:30]([NH:34][C:35]([C:37]3([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:39][CH2:38]3)=[O:36])=[C:29]([F:50])[CH:28]=2)[CH:23]=[CH:22][N:21]=1)=[O:18])C1C=CC=CC=1.Cl.[OH:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:50][C:29]1[CH:28]=[C:27]([O:26][C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:17]([N:55]3[CH2:56][CH2:57][C@@H:53]([OH:52])[CH2:54]3)=[O:18])[CH:25]=2)[C:32]([F:33])=[CH:31][C:30]=1[NH:34][C:35]([C:37]1([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])[CH2:38][CH2:39]1)=[O:36]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Reaction time: 5 h
Yield: 90.2 %

Procedure:
N,N-Diisopropylethylamine (0.249 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), (R)-3-hydroxypyrrolidine hydrochloride (88.2 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 hours. (R)-3-Hydroxypyrrolidine hydrochloride (44.1 mg) and N,N-diisopropylethylamine (0.125 ml) were added at room temperature, and the mixture was stirred for 15 hours and 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture to quench the reaction, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (50 ml) and (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (178.2 mg, 90%) as a white solid.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:14][C:15]1[CH:20]([C:21]([OH:23])=[O:22])[N:19]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:18]2[S:17][CH:16]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:29]1([CH2:28][C:27]([NH:26][CH:25]2[C:24](=[O:36])[N:19]3[CH:20]([C:21]([OH:23])=[O:22])[C:15]([CH2:14][C:9]4[C:1]([OH:2])=[CH:3][C:4]([OH:5])=[CH:6][C:7]=4[OH:8])=[CH:16][S:17][C@H:18]23)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Oc1cc(O)cc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3c(O)cc(O)cc3O)=CS[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 0.063 g of phloroglucinol in 0.3 ml of trifluoroacetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, and the solution is left to stand for 30 minutes at room temperature and diluted with an equal quantity of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 7-(N-Phenylacetyl-amino)-3-(2,4,6-trihydroxy-benzyl)-ceph-2-em-4ξ-carboxylic acid is thus obtained, showing the following Rf values in a thin layer chromatogram (silica gel): 0.73 (system n-butanol/acetic acid/water, 67:10:23) and 0.55 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [CH3:1][N:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:3]1[C:8]([CH:9](O)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][CH:9]([C:8]1[C:3]([N:2]([CH3:1])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN(c1cccnc1)c1ncccc1C(O)C(c1cccnc1)c1cccnc1
Solvent: ClCCl
Product: CN(c1cccnc1)c1ncccc1C(F)C(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of 1-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-2,2-dipyridin-3-ylethanol (31 mg) in 1.5 mL of CH2Cl2 was added DAST (20 mg). After 2 h stirring at room temperature, then reaction was cooled to 0 C and quenched with saturated aqueous sodium bicarbonate. then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and purified by reverse phase HPLC to give 6 mg of 3-(1-fluoro-2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine. 1H NMR (CDCl3) δ 8.48 (2H, t, J=4.9 Hz), 8.45 (1H, dd, J=4.9, 2.0 Hz), 8.33 (2H, d, 20.5 Hz), 8.22 (1H, d, J=3.9 Hz), 8.12 (1H, s), 7.55 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=8.1 Hz), 7.46 (1H, dd, J=8.1, 1.7 Hz), 7.23-7.11 (4H, m), 7.02-7.00 (1H, m), 6.10 (1H, dd, J=46.4, 4.1 Hz), 4.32 (1H, dd, J=26.4, 5.1 Hz), 3.28 (3H, s).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Pr+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Pr+3]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 24 h
Yield: 18.1 %

Procedure:
Praseodymium (III) trifluoromethanesulfonate (3.53 g as a wet solid) and para-toluic acid (1.36 g) were refluxed together in 125 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 24 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give crude 4,4′-dimethylbenzophenone (0.65 g, 31% yield) as a cream-colored crystalline solid. This was then recrystallized from methanol to give white needles of pure 4,4′ dimethylbenzophenone (0.19 g,9% yield) (M.P. 90.5-91.5° C.).
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>C(O)(C)C>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12
Reactant: Nc1cccc(Br)c1
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2c3c(cc4c2=NCN=C4)=NC=N3)c1
Yield: 104.5 %

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.5 g, 1.6 mmol) [Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and 3-bromoaniline hydrochloride (0.4 g, 1.9 mmol) in isopropanol (200 mL) is heated under reflux for 1 h to give a precipitate of 4-(3-bromoanilino)-6H-imidazo[4,5-g]quinazoline hydrochloride (0.63 g, 72 %). 1H NMR (DMSO) δ9.93 (1H, brs), 9.01 (1H, s), 8.66 (2H, s), 8.39 (1H, s), 8.04 (2H, m), 7.39 (1H, t, J=7.9 Hz), 7.31 (1H, brd, J=8.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH2:39])O1>COCCOC.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>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: COc1cc(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 13 %

Procedure:
Method 26 was followed using 4-chloro-N,N-di-BOC-6-methoxypyrimidin-2-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (0.07M) at 90° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) afforded 4-(3-aminopyridin-4-yl)-6-methoxy-N,N-di-BOC-pyrimidin-2-amine in 13% yield). LCMS (m/z): 418.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccncc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.031 g, 0.09 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.020 g, 0.14 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was triturated with water, and the precipitate was collected by filtration, washed with water, ethanol, and diethyl ether. This material was further purified on a 10 g isolute silica column using a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v/v; 1:1) as eluant. The title compound was obtained as a pale yellow solid (0.007 g, 18%); 1H-NMR (500 MHz, DMSO-d6) 2.61 (br s, 4H, piperazine N(CH2)2), 3.71 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2), 3.83 (s, 3H, OMe), 7.09 (d, J=8.85 Hz, 2H) and 8.12 (d, J=8.80 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.40 (d, J=5.86 Hz, 2H), and 8.54 (d, J=4.48 Hz, 2H) (pyrid-4-yl protons), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.37 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)=[O:15]>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>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:14]=[O:15]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Clc1cnccn1
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: O=Cc1ccccc1-c1cnccn1

Procedure:
A solution of Pd(PPh3)4 (330 mg, 0.28 mmol) and chloropyrazine (987 μL, 11.0 mmol) in anhydrous DME (60 mL) was stirred for 20 min at room temperature under N2 atmosphere. The resulting red-orange mixture was treated with a solution of Na2CO3 (1.05 mg, 3.30 mmol) in H2O (15 ml), followed by 2-formylbenzene boronic acid (1.50 mg, 9.90 mmol), resulting in a white precipitate. The mixture was heated to reflux for 1.5 h. The DME was then removed in vacuo and the residual suspension was extracted twice with CH2Cl2. The combined organic extracts were dried (anhydrous Na2SO4) and concentrated to give the title compound as a red-orange solid which was dried in vacuo for 16 h and used without further purification. LCMS (M+H): 185.02.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:16])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:16][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: Oc1nc(-c2cccs2)ncc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cnc(-c2cccs2)nc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-(thiophen-2-yl)pyrimidin-4-ol (90 mg, 0.42 mmol, 1.0 equiv.), POBr3 (364 mg, 1.27 mmol, 3.0 equiv.) and N,N-dimethylbenzenamine (103 mg, 0.85 mmol, 2.0 equiv.) in toluene (5 mL) was stirred at 100° C. for 1 h, then poured into crashed ice. The mixture was extracted with ethyl acetate. The combined organic layers were washed over saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford 4-bromo-5-chloro-2-(thiophen-2-yl)pyrimidine, which was directly used for the next step. LC-MS (m/z)=275.0 [M+H]+.