Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc(N)cc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)cc1
Temperature: 90 °C

Procedure:
To 0.30 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(4-aminophenyl)pyridine was added 6 ml of hydrazine monohydrate, and the mixture was heated at 90° C. for 30 minutes. The reaction mixture was poured into 150 ml of ice-water and the mixture was adjusted to pH 6 with acetic acid. The resultant precipitate was collected by filtration, and washed with water, followed by reprecipitation from DMSO/H2O, whereby 0.21 g of the title compound was obtained as orange powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=2)[NH:6][CH:5]=1.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(Cl)Cl>CN(C=O)C.O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=2)[N:6]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1cnc2[nH]cc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3nc(CNC(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.8 %

Procedure:
A flask was charged with NaH (60 wt % in mineral oil, 0.025 g, 0.64 mmol) in DMF (2.0 mL). The suspension was cooled to about 0° C., followed by the addition of a solution of tert-butyl (7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (0.16 g, 0.49 mmol) in DMF (2.0 mL). The mixture was stirred at about 0° C. for about 10 min and then at rt for about 20 min. The mixture was cooled to about 0° C. followed by the addition of a solution of TsCl (0.112 g, 0.587 mmol) in DMF (1.0 mL). The mixture was stirred at 0° C. for about 20 min and warmed to rt and stirred for about 1 h. To the mixture were added DCM (10 mL) and water (10 mL). The organic layer was isolated and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. EtOAc (10 mL) and heptane (10 mL) were added and then the mixture was concentrated under reduced pressure to give tert-butyl (7-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (0.24 g, 91%): LC/MS (Table 2, Method c) Rf=1.59 min; MS m/z 481 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccccc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.612 mmol) in NMP (2 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a pink solid (71 mg, 27%). 1H NMR (DMSO-d6) δ: 10.94 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.08-7.38 (m, 5H), 6.07 (s, 1H), 4.28 (br. s., 2H), 3.86 (br. s., 1H), 3.08-3.24 (m, 2H), 2.38-2.46 (m, 1H), 2.35 (s, 3H), 1.85-1.95 (m, 2H), 1.82 (s, 3H), 1.45-1.64 (m, 3H), 1.36-1.43 (m, 1H). ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[C:3]([C:2](=[O:1])[CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:19]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred benzyl 3-oxobutanoate (1.1 g, 5.7 mmol), dimethylformamide dimethylacetal (1 mL, 7.4 mmol) was added dropwise at room temperature. The mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3×10 mL) to provide compound D27-1 as a brown oil (1.4 g, quant.).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[O:23]1[CH2:24][CH2:25][CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Temperature: 100 °C
Yield: 16.4 %

Procedure:
In 8 mL of N,N-dimethylformamide were combined 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.75 g, 3.87 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (1.04 g, 5.80 mmol), and Cs2CO3 (2.01 g, 6.18 mmol) in a glass bomb and then sealed under nitrogen and heated to 100° C. After one hour the reaction was cooled and water was added to dissolve all solids. The solution was diluted with water and then extracted with EtOAc (250 mL). The organic layer was then washed with water and brine. The combined aqueous layer was then extracted with EtOAc (200 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was dried overnight on high vacuum. The crude was purified by way of silica gel chromatography eluting with a gradient of 15-25% EtOAc in DCM to afford 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.176 g, 0.633 mmol, 16.4% yield). MS (apci) m/z=279.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=1
Reactant: COc1cccc(CCl)c1
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(OC)c1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 0.699 g (2.0 mmol) of the product of Example 62 in 5 mL of DMF was added 0.096 g (2.4 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 0.376 g (2.4 mmol) of m-methoxybenzyl chloride and 0.089 g (0.24 mmol) of tetrabutylammonium iodide were added. The reaction mixure was stirred for 18 hr at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentad in vacuo. The crude solid was triturated with hexane to provide 0.768 g (82%) of the desired product as white solid. Electrospray Mass Spec 470.3 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
Into a suspension of methyl 8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-8-oxooctanoate (420 mg, 0.73 mmol) in THF/H2O (2/1) (15 mL) was added NaOH (1.0 N, 3.6 mL). The resulting solution was stirred at rt for 2.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (340 mg, 82%) in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(OC(=O)[N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([CH3:43])([CH3:42])[C:33]([N:35]3[CH:39]4[CH2:40][CH2:41][CH:36]3[CH2:37][CH2:38]4)=[O:34])[CH:30]=2)[NH:25][C:24]=1[C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[CH:45]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.[H][H]>[Pd].C(Cl)Cl.CO>[CH:36]12[N:35]([C:33](=[O:34])[C:32]([C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([C:44]3[CH:45]=[C:46]([CH3:51])[CH:47]=[C:48]([CH3:50])[CH:49]=3)=[C:23]4[CH2:22][CH2:21][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)([CH3:43])[CH3:42])[CH:39]([CH2:38][CH2:37]1)[CH2:40][CH2:41]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCCCc2cccnc2)C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCCCCc2cccnc2)c1

Procedure:
A mixture of 80.2 mg (0.115 mmol) of [2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(pyridin-3yl)butyl]carbamic acid benzyl ester, 40 mg of 10% palladium on carbon, 4 mL of absolute ethanol, and 4 mL of ethyl acetate was shaken with hydrogen (46 psig) in a pressure vessel for 6 hours. The catalyst was removed by filtration through Celite under nitrogen, and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 4 Analtech tapered silica gel plates (20×20 cm), which were developed in 92.5:7.5:0.75 CH2Cl2-MeOH-concentrated NH4OH. The product band from each plate was isolated, combined, and extracted with 92.5:7.5:0.75 CH2C12-MeOH-concentrated NH4OH. Concentration of the extracts in vacuo yielded 53.8 mg (81%) of a pale yellow, stiff gum or glass; essentially homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2-MeOH-concentrated MeOH-concentrated NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=563.5 (M+H).
Reaction SMILES: Cl.[C:2](=[NH:9])([O:6][CH2:7][CH3:8])[CH:3]([CH3:5])[CH3:4].N1C(C)=CC(C)=CC=1C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([N:9]=[C:2]([O:6][CH2:7][CH3:8])[CH:3]([CH3:5])[CH3:4])=[O:21])[CH3:24]
Reactant: CCOC(=N)C(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(OCC)C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Ethyl isobutyrimidate hydrochloride (1.8 g, 11.9 mmol) was suspended in hexanes (29.7 mL) and cooled to 0° C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylisobutyrimidate (2.2 g, 99%) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 4.09 (q, J=7.1 Hz, 2H), 4.03 (q, J=7.1 Hz, 2H), 2.65-2.64 (m, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H), 1.07 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[F:63][C:64]([F:75])([F:74])C1C=C(C=CC=1)C(Cl)=O>ClCCl>[F:63][C:64]([F:75])([F:74])[C:33]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.085 g, 0.28 mmol), triethylamine (0.10 mL, 0.72 mmol) and 3-(trifluoromethyl)-benzoyl chloride (0.065 g, 0.31 mmol) in dichloromethane (5 mL) gave 3-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.12 g) as a yellow oil. MS m/z 478 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OCC)(=O)C>CC#N>[N:28]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 43 %

Procedure:
To a slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) and K2CO3 (56 mg, 0.403 mmol) in MeCN (5 mL), piperidine (35 μL, 0.353 mmol) was added and the reaction mixture was stirred at reflux for 18 hrs. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (Flash Master, Isolute 5 g silica, gradient 0-5 min, 100% hexane and then 0-100% ethyl acetate over 40 min) to afford 2-(piperidin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (50 mg, 42% yield). LCMS calculated for C21H22N4O (M+H): 347.18. found 347. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.88 (1H, br. s), 9.48 (1H, s), 8.54 (1H, m), 8.12-8.10 (2H, m), 7.98 (1H, d, J=7 Hz), 7.91-7.81 (3H, m), 7.52 (1H, m), 3.12 (2H, s), 2.55-2.53 (4H, m), 1.61-1.55 (4H, m), 1.42-1.36 (2H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[C:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=2)(O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:43]>CO.O.O1CCOCC1>[ClH:43].[ClH:43].[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:17]2[NH:18][CH:19]=[C:15]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:16]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCN(Cc3ccccc3)CC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2[nH]cc(C3=CCNCC3)c2-c2ccncc2)cc1
Yield: 80 %

Procedure:
249 mg (0.689 mmol) of 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 9 above] were dissolved in a mixture of 2.5 ml of methanol and 2.5 ml of water, after which 2.43 ml (9.646 mmol) of a 4 N solution of hydrogen chloride in dioxane were added to the solution. The resulting mixture was heated under reflux for 11 hours, after which the reaction mixture was concentrated by evaporation under reduced pressure and the residual solid was washed with hot isopropanol to give 216 mg (yield 80%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]2[CH:20]=[C:21](Br)[S:22][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.Cl>C(O)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]2[S:22][C:21]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:9]1=2
Reactant: CCOC(=O)c1cc2sc(Br)cc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: OB(O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2sc(-c3cccs3)cc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Tetrakis-(triphenylphosphine)palladium (0) (20 mg) was added to a degassed solution of ethyl4-(3,4-dichlorobenzyl)-2-bromothieno[3,2-b]pyrrole-5-carboxylate (0.1 g) and thiophene-2-boronic acid (34 mg) in ethanol (1 ml), toluene (1 ml) and aqueous potassium carbonate (2N, 1 ml), and the reaction stirred at 80° C. under an argon atmosphere for 6 hours. The reaction was cooled, poured into 2N HCl and extracted with ether. Combined organic extracts were cried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using isohexane to isohexane-25% ethyl acetate as eluent to give the product as a pale yellow crystalline solid (77 mg, 77%), M/z (+) 435 (MH+), 276, 204, 159, 127.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O:14][P:15]([CH2:21][P:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])[O:16]C(C)C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:48])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[F:48][O:14][P:15]([CH2:21][P:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37])([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])[OH:16]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: C=CCCCCCCCCCP(=O)(CP(=O)(OC(C)C)OC(C)C)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCCCCP(=O)(CP(=O)(O)OF)OCC
Temperature: -78 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A 1 M solution of sodium bistrimethylsilylamide in tetrahydrofuran (30 mL, 30 mmol) was added dropwise with stirring to ((10-undecenyl)-ethoxyphosphinyl) methylphosphonic acid diisopropyl ester (11 g, 25.9 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. under a nitrogen atmosphere. After the addition was complete (15 minutes) the solution was stirred for 45 minutes after which n-fluorobenzenesulfonimide (10 g, 31.7 mmol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction was stirred for 3 hours at −78° C. The reaction was then warmed to −50° C., and excess base was neutralized by the addition of saturated ammonium chloride. The mixture was warmed to room temperature and the volatiles were removed by rotary evaporation to give a creamy solid. The solid was dissolved in water (300 mL) and then extracted three times with ethyl acetate (350 mL). The organic layers were combined and extracted with saturated sodium bicarbonate (250 mL). The ethyl acetate layer was dried over sodium sulfate and volatiles were removed by rotary evaporation to give a viscous liquid. The liquid was purified by flash chromatography (500 g silica, ethyl acetate/ethanol=9.5/0.5) to give the desired product (3.1 g, 27% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.OO.Cl.C(O)(=[O:21])C>[OH-].[Na+]>[NH2:7][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([OH:15])=[O:21]
Reactant: CC(=O)O
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Agent: Cl
Agent: OO
Agent: [Na+]
Product: COc1cc(N)c(C(=O)O)c(OC)c1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a mixture of 4,6-dimethoxyindoline-2,3-dione (20.28 g, 97.9 mmol) in 30% NaOH solution (100 mL) at 100° C. was carefully dropped a 50% H2O2 solution. It was heated at 100° C. for 20 minutes. It was cooled down and neutralized by concentrated HCl to pH 8, followed by acetic acid to pH 5 to form a solid. It was filtered, washed with water, and dried under vacuum with P2O5 to afford 2-amino-4,6-dimethoxybenzoic acid as a yellow solid (15.034 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ 6.00 (d, 1H), 5.85 (d, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.41 (br, 2H); LC-MS (ESI) m/z 198 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:11](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: Cc1cc(C)c2oc(=O)[nH]c2c1

Procedure:
A mixture of 2-amino-4,6-dimethylphenol (412 mg, 3.00 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.50 mmol) in TIE (15 mL) was heated at reflux for 3 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1.0 N aqueous HCl (2×), then brine, then the EtOAc was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=164 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH:18]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.C(Cl)Cl>[O:21]1[C:20]2([CH2:25][CH2:26][C:17]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=3)=[CH:18][CH2:19]2)[O:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1cnc(C2=CCC3(CC2)OCCO3)cn1
Yield: 57.4 %

Procedure:
To 5-bromopyrazin-2-amine (225 mg, 1.293 mmol) was added 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (482 mg, 1.810 mmol), PdCl2(dppf)-CH2Cl2 adduct (84 mg, 0.103 mmol), DME (3.5 mL) and then last sodium carbonate 2M (1.616 mL, 3.23 mmol). The reaction was microwaved at 120° C. for 15 min. To the reaction was added 80 mL of DCM, washed with water (1×), dried sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 12 gram column (solid load) eluting with 10-90% ethyl acetate and heptane. The desired fractions were concentrated to constant mass to give 173 mg of the desired product as free base used as is (56% yield). LCMS (m/z): 234.2 (MH+), 0.43 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 6.33 (s, 2H), 6.27 (t, J=3.9 Hz, 1H), 3.89 (s, 4H), 2.52 (d, J=1.6 Hz, 2H), 2.33 (br. s., 2H), 1.76 (t, J=6.7 Hz, 2H).