Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([I:8])=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:6]=[CH:7][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(I)cn1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Temperature: 100 °C
Reaction time: 66 h

Procedure:
2-bromo-5-iodopyrazine (503 mg, 1.77 mmol) and tert-butyl piperazine-1-carboxylate (355 mg, 1.91 mmol) were taken up in tBuOH (8 mL). iPr2NEt (400 μL, 2.3 mmol) was added and the stirred reaction mixture was heated to 100° C. After 66 h, the reaction mixture was cooled and was partitioned between EtOAc, water and brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to afford tert-butyl 4-(5-iodopyrazin-2-yl)piperazine-1-carboxylate 7.11.
Reaction SMILES: C(OC[N:9]1[C:17]2[C:16]([Cl:18])=[CH:15][C:14]([Cl:19])=[CH:13][C:12]=2[C:11]2[CH2:20][CH2:21][C:22]([C:28]([F:31])([F:30])[F:29])([O:23][Si](C)(C)C)[C:10]1=2)(=O)C(C)(C)C.[OH-].[K+]>C1COCC1.O>[Cl:18][C:16]1[C:17]2[NH:9][C:10]3[C:22]([C:28]([F:31])([F:29])[F:30])([OH:23])[CH2:21][CH2:20][C:11]=3[C:12]=2[CH:13]=[C:14]([Cl:19])[CH:15]=1
Reactant: CC(C)(C)C(=O)OCn1c2c(c3cc(Cl)cc(Cl)c31)CCC2(O[Si](C)(C)C)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 430 %

Procedure:
To (5,7-Dichloro-3-(trifluoromethyl)-3-(trimethylsilyloxy)-2,3-dihydrocyclopenta[b]indole-4(1H)-yl)methyl pivalate (0.32 g, 0.6 mmol) in THF (6.0 mL), cooled to 0° C., KOH (0.18 g, 3.2 mmol), in H2O (6.0 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 h, diluted with water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to afford the title compound as a white solid (0.80 g, 40%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.75 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1.5 Hz, 1H), 6.83 (s, 1H), 2.93-2.88 (m, 2H), 2.78-2.74 (m, 1H), 2.53-2.50 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:12])[CH3:11]>C(N(C(C)C)C(C)C)C.C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:24][CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[CH:27]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:25]=3)[CH2:19][CH2:20]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)Oc1cc(CN2CCC(N)CC2)cc(OC(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Oc1cc(CN2CCC(Nc3ncnc(Cl)c3N)CC2)cc(OC(C)C)c1
Yield: 20 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-5-ylamine (19.7 mg, 0.12 mmol, 1.0 equiv; commercially available) and 1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamine (46.0 mg, 0.15 mmol, 1.25 equiv; intermediate A3) in N-ethyl diisopropylamine (1.0 mL) and acetonitril (1.0 mL) was heated by microwave irradiation to 160° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.6 mg (20%) of the title compound. MS (ISP): 434.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([CH:34]1[CH2:38][CH:37]([N:39]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH:35]1[CH3:54])=[O:33]>CN(C=O)C>[CH2:47]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:37]1[CH2:38][CH:34]([C:32](=[O:33])[CH2:31][N:22]([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][N:13]([S:3]([C:6]4[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=4)(=[O:5])=[O:4])[C:17]3=[N:18][CH:19]=2)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:35]([CH3:54])[CH2:36]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)C(=O)OC(C)(C)C)cnc32)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45 mmol) in DMF (5 mL) was added a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol, Example #3, Step E) in DMF (5 mL) dropwise at about 0° C. The resulting mixture was stirred at this temperature for about 30 min and then added dropwise to a solution of 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.823 mmol, Preparation #R.1) in DMF (10 mL). The resulting mixture was stirred at about 0° C. for about 1 h and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc (100 mL each). The organic phase was dried over anhydrous MgSO4 and concd under reduced pressure to yield tert-butyl 2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=3.30 min; MS m/z 708 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=CC=1O)[C:5](O)=[O:6].[C:12]([Cl:17])(=O)[C:13](Cl)=[O:14].CN(C=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1O>ClCCl>[Cl:17][C:12]1[CH:2]=[CH:3][C:4]([C:5]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:6])=[CH:8][C:13]=1[OH:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(Cl)c(O)c1
Reaction time: 2 h

Procedure:
A suspension of 3-chloro-4-hydroxybenzoic acid (20.0 g, 11.6 mmol) in anhydrous dichloromethane (100 mL) was treated with oxalyl chloride (20 mL, 23.2 mmol) followed by few drops of DMF at 22° C. under argon. After 2 h stirring, the solution became clear, concentrated to dryness, dissolved in dichloromethane (50 mL) and added slowly to a solution of 2-aminophenol (12.6 g, 11.6 mmol) and TEA (9 mL, 11.6 mmol) in anhydrous DMC (50 mL). After 20 min stirring, filtered off salt, concentrated the mixture to afford 4-chloro-3-hydroxy-N-phenylbenzamide as a brown solid. MS (ESI) 264(M+H)+. 4-Chloro-3-hydroxy-N-phenylbenzamide (4 g, 15.2 mmol) was treated with POCl3 (5 mL) at reflux for 1 h. Concentrated and dissolved in dichloromethane (50 mL), washed with sat. NaHCO3 (3×25 mL) and sat. brine (3×25 mL), dried (MgSO4), concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 2:1 hexanes:EtOAc to afford 4-(1,3-benzoxazol-2-yl)-2-chlorophenol as a colorless solid. MS (ESI) 246(M+H)+. The solution of 4-(1,3-benzoxazol-2-yl)-2-methoxyphenol (800 mg, 3.3 mmol) in anhydrous DMF (10 mL) was treated with Cs2CO3 (1.1 g, 3.2 mmol) and N-phenyl trifluoromethanesulfonimide (1.2 g, 3.2 mmol) at 22° C. for 30 min. After which time it was quenched with sat. NaHCO3 (20 mL) and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. brine (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc to afford 4-(1,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate a colorless oil. MS (ESI) 378 (M+H)+. The solution of 4-(1,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate (150 mg, 0.4 mmol) in 6 mL of 2:1 DMF:H2O was degassed via Argon for 10 min. Then K2CO3 (137 mg, 0.99 mmol), Pd(Ph3P)4 (23 mg, 0.02 mmol), n-Bu4NBr (128 mg, 0.40 mmol) and 3-Pyridylboronic acid (73 mg, 0.60 mmol) were added at 22° C. The resulting mixture was then heated at 75° C. for 1 h under Argon. Cooled the reaction mixture to 22° C., then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes:EtOAc) the desired compound, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.75 (d, 1H), 6.68 (dd, 1H), 8.42 (d, 1H), 8.24 (dd, 1H), 7.89 (dt, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.52 (d, 1H), 7.42 (m, 3H). MS (ESI) 307 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23](=[O:24])[O:25][CH3:26]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution containing the product from Example 148E (0.17 mmol) in tetrahydrofuran (1.7 mL) were added the product from Example 1F (0.036 g, 0.190 mmol), DEPBT (0.077 g, 0.258 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on C18 column eluting with a gradient starting with water and ending with methanol to give the product (0.044 g, 37% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2 H), 2.67-2.79 (m, 3 H), 3.47 (s, 3 H), 3.59-3.67 (m, 1 H), 3.81 (d, J=9.6 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.02-4.21 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.9 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.45-7.55 (m, 4 H), 7.80 (d, J=8.5 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H), 8.54 (d, J=4.8 Hz, 1 H), 8.83 (d, J=1.8 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-chlorobenzoic acid (1.00 g, 4.25 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.[CH2:22]([C:24]1[NH:25][CH:26]=[CH:27][N:28]=1)[CH3:23]>>[CH3:16][C:17]1[N:18]=[CH:19][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH:21]=1.[CH2:22]([C:24]1[N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH:26]=[CH:27][N:28]=1)[CH3:23]
Reactant: Cc1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCc1ncc[nH]1
Product: CCc1nccn1CCCN1C(=O)c2ccccc2C1=O
Product: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)cn1

Procedure:
Following the procedure of this example, N-(3-bromopropyl)phthalimide with 4-methylimidazole and 2-ethylimidazole were used to produce respectively 2-[3-(4-methyl-1H-imidazol-1-yl)propyl]isoindole-1,3-(2H)-dione and 2-[3-(2-ethyl-1H-imidazol-1-yl)-propyl]isoindole-1,3(2H)-dione which again following the procedure of this example were converted respectively to (4-methyl-1H-imidazol-1-yl)-1-propanamine dihydrochloride and (2-ethyl-1H-imidazol-1-yl)-1-propanamine dihydrochloride which were then converted by the procedure of Example 1, using the appropriate acid chloride, to the products of Examples 21-27, listed in Table V.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH:16]=[CH2:15]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: C=CCBr
Product: C=CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]-indol-4(5H)-one is alkylated with allyl bromide to give 3.9 g of product, mp 67°-68°C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:28]=[C:29]([NH2:42])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.CCN(CC)CC>O1CCOCC1.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>[NH2:42][C:29]1[CH:30]=[CH:31][C:32]([C:17]2[C:9]3[O:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11](=[O:13])[C:10]=3[CH:14]=[CH:15][CH:16]=2)=[C:27]([F:26])[CH:28]=1
Reactant: O=c1nc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cccc3c(=O)nc(N4CCOCC4)oc23)c(F)c1
Temperature: 70 °C

Procedure:
To a mixture of trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-benzo[e][1,3]oxazin-8-yl ester, 3 (60 mg, 0.16 mmol, 1 eq), 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (47 mg, 0.20 mmol, 1.3 eq), Pd(PPh3)4 (7.6 mg, 0.007 mmol, 5 mol %) in dioxane (2 mL) and H2O (1mL) was added Et3N (66 mL, 0.48 mmol, 3 eq) dropwise. The reaction mixture was heated up in a pressure tube at 70° C. for 6 h. Upon cooling, the solution was partitioned between EtOAc (15 mL) and H2O (10 mL). The aqueous layer was further extracted with EtOAc (2×5 mL) and DCM (5 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuuo. The residue was further purified by silica gel column chromatography with EtOAc:MeOH (1:0-13:1) to yield the product, B, as a pale brown solid (47 mg, 87%). 1HNMR (400 MHz, CDCl3+10% MeOD) δH: 7.98 (dd, J=7.5, 1.5 Hz, 1H), 7.62 (dd, 1.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.12 (t, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.3 Hz, 1H), 6.52 (dd, J=12.5, 2.0 Hz, 1H), 3.49-3.90 (m, 10H). MS (ES+) 342.1 (100%, [M+H]+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of N-tert-butyl-2-(p-tolylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 176 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (402 mg, 272 μL, 3.53 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether. Purification by chromatography (silica, 20-40% of a 10:89.5:0.5 methanol:dichloromethane:ammonium hydroxide solution in dichloromethane) gave N-tert-butyl-2-(p-tolylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (17 mg, 52.6 μmol, 30%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.26 (s, 1H), 9.34 (s, 1H), 7.97 (s, 1H), 7.96 (d, J=3.3, 1 H), 7.76 (s, 1H), 7.57 (t, J=8.5, 2 H), 7.09 (d, J=8.1, 2 H), 2.26 (s, 3H), 1.44 (s, 9H); MS (EI/CI) m/z: 324.1 [M+H].
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH:2]([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC1CNc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CC1CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
1,2,3,4-Tetrahydro-3-methylquinoline (51 mg, 0.35 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.35 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 8.2 mg (12%) of 7-nitro-1,2,3,4,-tetrahydro-3-methylquinoline. Data for 7-nitro-1,2,3,4,-tetrahydro-3-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.25, 2.2, 1H), 7.27 (d, J=2.3, 1H), 7.01 (d, J=8.3, 1H), 4.19 (s, 1H), 3.33 (m, 1H), 2.94 (dd, J=10.1, 10.1, 1H), 2.86 (ddd, J=13.8, 4.7, 1.7, 1H), 2.46 (dd, J=16.6, 10.0, 1H), 2.05 (m, 1H), 1.06 (d, J=6.7, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1.[C:23](O)(=[O:26])[CH:24]=[CH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](N)C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(NC(=O)OC(C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of 114c (1.39 g, 4.22 mmol), acrylic acid (0.3 mL, 4.5 mmol), HATU (1.7 g, 4.5 mmol) and DIPEA (3.8 mL, 9 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 6-(3-acrylamidopiperidin-1-yl)pyridin-2-ylcarbamate 114d (880 mg, 60%) as brown oil. The material was used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2CN=1.S(=O)(=O)(O)O.N([O-])=[O:30].[Na+].[C:33](=[O:36])([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH3:23])=[N:21][N:22]=[C:11]1[CH2:33][OH:36])=[O:30]
Reactant: O=N[O-]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (34.3 g) was added to water (500 ml), and conc. sulfuric acid (74 ml) was dropwise added with vigorous stirring. The mixture was further stirred at 90° C. for 1 hour, and sodium nitrite (74 g) was added. Then, potassium carbonate was added to the reaction mixture to make the mixture alkaline. The mixture was extracted with ethyl acetate and washed with water. The mixture was dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-diisopropyl ether to give 26.06 g of 4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl-5-methyl[1,2,4]triazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH:16]=1)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH:28]1([C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH:16]=2)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(C2CC2)c1)OCC
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a solution of diethyl 3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylphosphonate (0.93 g, 1.99 mmol) and cyclopropylboronic acid (0.204 g, 2.38 mmol) in THF (5.6 mL) was added potassium phosphate (1.27 g, 5.99 mmol). The mixture was degassed by purging with argon. PdCl2(dppf2 (162.2 mg, 0.198 mmol) and water (0.11 mL) were added to the reaction mixture and the mixture was degassed again. The reaction was heated at 50° C. for 1 h. The reaction mixture was concentrated and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) to give the title compound (0.8 g, 94%). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 6.96 (d, J=9 Hz, 1H), 6.90 (s, 1H), 6.86 (s, 1H), 6.73 (s, 1H),), 4.02 (m, 4H), 3.14 (s, 1H), 3.10 (s, 1H), 1.87 (m, 1H), 1.24 (m, 6H), 0.96 (d, J=8.5 Hz, 2H), 0.69 (d, J=5 Hz, 2H); m/z (430.0, M+ H+).