Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH3:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].[CH2:17](I)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH3:15])[N:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ccc(SC)cc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)OCC

Procedure:
N-(4-Methylthiophenyl)alanine ethyl ester (10.0 g, 42.0 mmol), n-butyl iodide (7.9 g, 42 mmol) and potassium carbonate were added to 150 mL of acetonitrile and the mixture was heated at reflux for 48 h under a nitrogen atmosphere. The reaction mixture was cooled and then partitioned between 300 mL ethyl acetate and 200 mL brine. The organic layer was separated, washed with 100 mL brine, dried over anhyd. sodium sulfate, and concentrated at reduced pressure. The resulting oil was charged onto a silica gel column and eluted with heptane:THF (5:1). The desired ester was isolated as a yellow oil (3.0 g, 24%).
Reaction SMILES: Cl.N[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([SH:24])[N:17]=1.[OH-].[Na+]>O>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([S:24][C:18]2[N:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[N:19]=2)[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)nc(S)n1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
5.0 g of 2-amino-6-chlorobenzoic acid hydrochloride was converted to a diazonium salt with 2.3 g of sodium nitride and concentrated hydrochloric acid. Then, this diazonium salt was gradually dropwise added to a solution comprising 4.8 g of 4,6-dimethoxy-2-mercaptopyrimidine, 2.4 g of sodium hydroxide and 40 ml of water at 0° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. Concentrated hydrochloric acid was added to the reaction solution, and then, the mixture was extracted with ethyl acetate. The extract was dried, and then the solvent was distilled off under reduced pressure. The residue thereby obtained was purified by column chromatography to obtain 1.8 g of the desired compound as ocher powder.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:34]=[N:35][C:30]([CH:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:31][CH:32]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(C2CCN(C)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(C4CCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
Trimethylaluminium (2 M in toluene, 1.168 ml, 2.34 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (231 mg, 0.93 mmol) and methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (220 mg, 0.93 mmol) in anhydrous toluene (4.671 ml) at 25° C. The resulting solution was stirred at 60° C. for 2 h. The reaction mixture was poured into methanol (100 mL), acidified with 2M HCl and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (166 mg, 39%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7]([NH:12][C@@H:13]2[CH2:18][C@@H:17]3[CH2:19][C@@H:15]([C:16]3([CH3:21])[CH3:20])[C@H:14]2[CH3:22])[CH:6]=[N:5]1.C(N(CC)CC)C.[N:30]1[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1.O>ClCCl>[Br:11][C:8]1[C:9](=[O:10])[N:4]([CH2:3][CH2:2][NH:1][C:36]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[O:37])[N:5]=[CH:6][C:7]=1[NH:12][C@@H:13]1[CH2:18][C@@H:17]2[CH2:19][C@@H:15]([C:16]2([CH3:21])[CH3:20])[C@H:14]1[CH3:22]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN)c(=O)c1Br)C2(C)C
Reactant: O=C(Cl)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCNC(=O)c3ccncc3)c(=O)c1Br)C2(C)C
Yield: 52.8 %

Procedure:
2-(2-Aminoethyl)-4-bromo-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (28 mg, 0.0758 mmol) and triethylamine (21 μL, 0.152 mmol) in dichloromethane (1 mL) were stirred with pyridine-4-carbonyl chloride (20 mg, 0.112 mmol) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to give the desired product (19 mg, 52% yield).
Reaction SMILES: COC(C1C(C)=CC(C(O)=O)=CC=1C)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)=O.[CH3:45][C:46]1[CH:47]=[C:48]([N:57]=[C:58]=[O:59])[CH:49]=[C:50]([CH3:56])[C:51]=1[C:52]([O:54][CH3:55])=[O:53].Cl.[NH:61]1[C:69]2[CH:68]=[CH:67][CH:66]=[C:65]([CH2:70][NH2:71])[C:64]=2[CH:63]=[CH:62]1>C1C=CC=CC=1>[NH:61]1[C:69]2[C:64](=[C:65]([CH2:70][NH:71][C:58]([NH:57][C:48]3[CH:49]=[C:50]([CH3:56])[C:51]([C:52]([O:54][CH3:55])=[O:53])=[C:46]([CH3:45])[CH:47]=3)=[O:59])[CH:66]=[CH:67][CH:68]=2)[CH:63]=[CH:62]1
Reactant: COC(=O)c1c(C)cc(N=C=O)cc1C
Reactant: NCc1cccc2[nH]ccc12
Agent: COC(=O)c1c(C)cc(C(=O)O)cc1C
Agent: Cl
Agent: O=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: COC(=O)c1c(C)cc(NC(=O)NCc2cccc3[nH]ccc23)cc1C
Temperature: 75 °C

Procedure:
In an inert atmosphere, a solution of 4-(methoxycarbonyl)-3,5-dimethylbenzoic acid (2.08 g, 10 mmol), diphenylphosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) is stirred at room temperature for 1 h, then the reaction temperature is slowly raised to 75° C. The reaction is held at that temperature until the evolution of gas (CO2) is no longer evident and the reaction solution containing 3,5-dimethyl-4-(methoxycarbonyl)phenylisocyanate is cooled to 40° C. Another portion of diisopropylethylamine (1.92 mL, 11 mmol) is added, followed by 1H-indole-4-methanamine hydrochloride salt (Example 68; 2.95 g, 11 mmol) and the solution is stirred and heated at reflux under argon overnight. The reaction mixture is cooled, diluted with benzene (50 mL) and washed in turn with 1N hydrochloric acid (50 mL) and dilute brine. The aqueous layers are re-extracted with benzene and the combined extracts are dried (MgSO4) and evaporated under reduced pressure. The product is purified if necessary by crystallization or by chromatography over silica gel using increasing concentrations of ethyl acetate in hexane to furnish the urea, 4-[[(1H-indol-4-yl)methylamino]carbonyl]amino-2,6-dimethylbenzoic acid, methyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:19]
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
To 0.88 g (~0.01 mole) of freshly prepared N-methylaniline (b.p. 196° C.) is added 2.0 g (~0.01 mole) of 2-trifluoromethylbenzene-sulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is then added dropwise with stirring until the solution is slightly alkaline. The 2-trifluoromethyl-N-methylbenzene-sulfonanilide is formed as a viscous light brown liquid. It is next washed with water several times until the wash water is neutral to litmus paper, and the viscous light brown liquid is extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of light brown oil is 2.5 g (96% yield). 1H NMR (deuterioacetone): δ7.8.2 (m, 9 ArH), 3.2 (s, 3H, N--CH3)
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:33])[C:29](=[O:32])[CH2:30]Cl.O>CN(C)C=O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([O:5][CH2:30][C:29](=[O:32])[N:28]([CH3:33])[CH3:27])=[O:4]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)O)cc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)OCC(=O)N(C)C)cc1C2
Temperature: 75 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Under a nitrogen atmosphere, 5.4 g of α,2-dimethyl-5H-[1]-benzopyrano [2,3-b]pyridine-7-acetic acid is dissolved in 22 ml of dimethylformamide, whereafter 1.9 g of potassium carbonate and 2.7 g of N,N-dimethyl-2-chloroacetamide are added, and the mixture is stirred at 75° C. for 2 hours. Under cooling with ice, 50 ml of water is added to the resulting reaction mixture. The precipitated crystals are collected by filtration and washed with water, and then recrystallized from isopropyl alcohol to obtain 6.4 g of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7acetate as white crystals having a melting point of 150° to 151° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:18](=[O:35])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=2)[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:17][C:18](=[O:35])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2c(c1)N=C(c1cccc(-c3ccnc(C)c3)c1)CC(=O)N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M55) (213 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (120 mg).
Reaction SMILES: C(OC([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12]([CH:18]4[CH2:20][CH2:19]4)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH:18]1([CH:12]2[C:11]3[C:10]4[CH2:21][CH2:22][NH:6][CH2:7][CH2:8][C:9]=4[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13]2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C1CC1)CC3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: c1cc2c(c3c1CCNCC3)C(C1CC1)CC2
Temperature: 60 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
Into a 20 ml vial, the product from step (b) (103 mg, 0.394 mmol) in CHCl3 (2 ml) was placed. To this solution, TMSI (468 μL, 3.44 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours and then at room temperature for 16 hours. The volatiles were evaporated in vacuo and 2M HCl (5 ml) and water (25 ml) were added. The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title product as a yellow oil (53 mg). 1H NMR (300 MHz, CDCl3) δ 6.99-6.91 (m, 2H); 3.09-2.92 (m, 8H); 2.79-2.71 (m, 2H); 2.24-2.14 (m, 1H); 2.05-1.98 (m, 1H); 1.30-1.21 (m, 2H); 0.88-0.78 (m, 1H); 0.51-0.44 (m, 2H); 0.31-0.026 (m, 1H); 0.23-0.17 (m, 1H); MS: ESI (positive): 228, (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CNC.C(N(CC)CC)C>C1COCC1>[CH3:14][N:15]([CH3:16])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)C)cc1
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a soln. of 4-(methoxycarbonyl)benzoic acid (100 mg, 0.555 mmol) in THF (5 ml) was added HATU (211 mg, 0.555 mmol), dimethylamine (0.278 ml, 0.555 mmol) and triethylamine (0.077 ml, 0.555 mmol) at r.t. The mixture was stirred at r.t for 4 hrs. Evaporated to remove the solvent. The residue was dissolved in EtOAc (10 ml), washed w/water (3×), brine. Dried (Na2SO4), and evaporated to afford methyl 4-(dimethylcarbamoyl)benzoate (100 mg, 0.458 mmol, 83% yield) as solid. 1H-NMR (CD3OD, 500 MHz): δ 8.10 (1H, d, J=6.4 Hz), 7.55 (1H, d, J=6.4 Hz), 3.94 (3H, s), 3.13 (3H, s), 2.99 (3H, s). m/e (M+H): 208.1
Reaction SMILES: [SH2:1].CC(C)([O-])C.[K+].[CH2:8]([C:10]1O[C:12]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[C:15](=[O:25])[C:13]=2[N:14]=1)[CH3:9]>CN(C)C=O>[CH2:8]([C:10]1[S:1][C:12]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[C:15](=[O:25])[C:13]=2[N:14]=1)[CH3:9]
Reactant: S
Reactant: CCc1nc2c(o1)CCc1cc(C)ccc1C2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(s1)CCc1cc(C)ccc1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen sulphide was passed through a suspension of potassium tert-butoxide (9.31 g) in N,N-dimethylformamide (80 ml) at 5° C. until the mixture was saturated. The product from example 1 step (v) (5.0 g) was added and the reaction mixture stirred at room temperature for 2 h. The mixture was poured onto ice, acidified to pH3 and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate in isohexane.
Reaction SMILES: N[C:2]1[CH:11]=[C:10](S(O)(=O)=O)[CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[CH:5][C:6](S(O)(=O)=O)=[CH:7]2.ClC1N=C(Cl)N=C(Cl)N=1>>[CH:10]1[CH:11]=[CH:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[OH:20])[CH:9]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: Clc1nc(Cl)nc(Cl)n1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 31.9 parts of 5-amino-4-hydroxynaphthalene-2,7-disulfonic acid was condensed with 18.4 parts of 2,4,6-trichloro-s-triazine according to a normal method and the resultant condensate was condensed with 28.1 parts of 3-(2-sulfate ethylsulfonyl)aniline according to a normal method to obtain a naphthol derivative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][CH2:18][CH3:19])[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:34]([NH:37][CH:38](C)C)(C)[CH3:35].O>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:35]=[CH:34][N:37]=[CH:38][CH:19]=3)[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)NC(C)C
Reactant: CCSc1nc(-c2ccc(OC)c(OC)c2)cc2nccn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(-c2cc3nccn3c(Sc3ccncc3)n2)cc1OC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
7-(3,4-Dimethoxy-phenyl)-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine (335 mg, 1.06 mmol) was dissolved in trifluoroacetic acid (TFA, 5 ml). After 5 min the TFA was evaporated. The residue was dissolved in 10 ml CH2Cl2. The solution was cooled to 0° C. and m-CPBA (70%, 524 mg, 2.12 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 5 h. Diisopropylamine (598 mg, 4.63 mmol) and thiol (254 mg, 2.28 mmol) were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extraction was carried out with CHCl3. The organic layer was washed with brine, sat. NaHCO3, brine and dried over Na2SO4. The organic layer was then concentrated to give the crude product of 7-(3,4-Dimethoxy-phenyl)-5-(pyridin-4-ylsulfanyl)-imidazo[1,2-c]pyrimidine which was purified by column chromatography (160 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[C:14]([N:16]([CH3:32])[C:17](=[O:31])[C:18]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]([CH3:30])[CH:20]=1)=[O:15]>CN(C=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]1[CH:18]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]([CH3:30])[CH:20]=2)[C:17](=[O:31])[N:16]([CH3:32])[C:14]1=[O:15]
Reactant: COc1ccc2c(c1)c(C1=C(c3cn(C)c4ccc(OC)cc34)C(=O)N(C)C1=O)cn2C
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C1C(=O)N(C)C(=O)C1c1cn(C)c3ccc(OC)cc13)cn2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
To a solution of 2,3-bis(5-methoxy-1-methyl-1H-indol-3-yl)-N-methylmaleimide (70 mg, 0.16 mmol) in DMF (2 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (42 mg, 60.4%) as pale red solids.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([NH2:26])[N:18]=2)=[CH:9][C:8]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].[Br:35][CH2:36][C:37](Cl)=[O:38]>CCOC(C)=O>[NH2:26][C:19]1[N:18]=[C:17]([NH:16][CH2:15][CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:37](=[O:38])[CH2:36][Br:35])=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[CH:9]=2)[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(NCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1nc(NCCNc2ccc(NC(=O)CBr)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Aqueous NaHCO3 (8 eq) was added to the stirred solution of [4-amino-3-(2,4-dichlorophenyl)phenyl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine (1 eq) in EtOAc at room temperature. 2-bromoacetyl chloride (1.5 eq) in minimal EtOAc was added slowly to the vigorously stirred reaction solution. The reaction was monitored by LC/MS and determined to be complete within 30 min. The organic layer was separated and washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-bromoacetamide as a dark yellow glass in 76% yield (˜90% pure, LC/MS m/z 555.2 MH+). The product was stored at −4° C. to avoid decomposition.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:3]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([NH:12][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)OC(C)(C)C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Nitrogen was bubbled into a mixture of methyl 4-bromo-2-(tert-butoxycarbonylamino)benzoate (0.62 g, 1.878 mmol), tert-butyl piperazine-1-carboxylate (0.350 g, 1.878 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.045 g, 0.094 mmol) and cesium carbonate (1.835 g, 5.63 mmol) in toluene (4 mL) for 10 min., followed by the addition of diacetoxypalladium (0.013 g, 0.056 mmol). The reaction mixture was stirred at 110° C. for two hours. The reaction mixture was cooled to RT. Water and ethyl acetate (30 mL/30 mL) were added. The two layers were separated in a separatory funnel The aqueous layer was extracted one more time with 30 mL of ethyl acetate. The product was purified by flash chromatography (1% EtOAc/DCM, Rf 0.44) to give 0.56 g (69% yield) of tert-Butyl 4-(3-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate. 1H-NMR (CDCl3, 400 MHz): δ 10.48 (1H, s), 8.01 (1H, d, J=2.5 Hz), 7.87 (1H, d, J=9.0 Hz), 6.46 (1H, dd, J1=9.0 Hz, J2=2.5 Hz), 3.86 (3H, s), 3.57 (4H, t, J=5.0 Hz), 3.36 (4H, t, J=5.0 Hz), 1.53 (9H, s), 1.49 (9H, s).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccnc(F)c4)nc3s2)cc1
Yield: 38 %

Procedure:
The titled compound (yield=38%, light yellow solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 2F (Example 2) and 2-fluoropyridin-4-ylboronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.49 (d, J=3.03 Hz, 2H) 4.78 (br. s., 1H) 7.59 (d, J=8.59 Hz, 2H) 7.91 (s, 1H) 8.06-8.16 (m, 3H) 8.27-8.36 (m, 2H) 8.38 (d, J=5.31 Hz, 1H) 13.11 (s, 1H); ESI-MS: m/z 423.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:18])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([CH3:18])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C[C@@H](CCN1CCOCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)CCN1CCOCC1
Temperature: 25 °C

Procedure:
The product of example 22 (c) (0.41 g, 1.59 mmol) was dissolved in CH2Cl2 (10 mL) and cooled in an ice bath while stirring under argon. A solution of trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) was added and the mixture allowed to warm to room temperature for 1 h. The solvents were evaporated to give the title compound as an oil. ES (+) MS m/e=159 (MH+)