Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:36][Mg]I>>[OH:17][C:8]([CH3:36])([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: C[Mg]I
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(=O)CCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(C)(O)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 115, Step 1, using 1-{4′-[3-methyl-4-(2-oxo-4-phenyl-butyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and methylmagnesium iodide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=O)[CH3:2].[CH3:18][NH:19][NH2:20]>C(Cl)CCl>[CH3:18][N:19]1[C:1]([CH3:2])=[C:4]2[CH:5]=[N:6][C:7]3[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]2=[N:20]1
Reactant: CNN
Reactant: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Solvent: ClCCCl
Product: Cc1c2cnc3c([N+](=O)[O-])cccc3c2nn1C
Yield: 45.2 %

Procedure:
A mixture of 3-acetyl-4-chloro-8-nitroquinoline (140 mg) and methylhydrazine (77.2 mg) in ethylene chloride was refluxed for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (methanol-dichloroethane) to give 2,3-dimethyl-6-nitro-2H-pyrazolo[4,3-c]quinoline (61.2 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:7]=[C:3]2[CH3:2])=[CH:17][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccccc2)c[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)cn1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-4-phenyl-1H-imidazole HCl salt (1.51 g, 7.75 mmol), 4-chlorobenzyl bromide (1.75 g, 8.53 mmol) and NaH (745 mg, 18.6 mmol) in DMF (20 mL) is stirred at RT. After completion the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; ES-MS: M+=283.1: At Ret=3.93 min.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:7][CH2:6]2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.[F-].[Cs+]>CN(C)C=O.O>[CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Reactant: BrCC1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(CC2CC2)CC=C(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-triisopropylsilanylsulfanylcyclohex-3-enecarbonitrile (20.5 g, 58.5 mmol) and (bromomethyl)cyclopropane (15.8 g, 117 mmol) in anhydrous N,N-dimethylformamide (65 ml) was added cesium fluoride (17.8 g, 117 mmol) and the mixture left to stir at ambient temperature for 15 hours. The mixture was diluted with water (500 ml) and extracted with diethyl ether (3×200 ml). The combined organic layer was washed with water (2×300 ml) and brine (200 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to give an orange oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (10-40%). Collecting appropriate fractions gave a colourless oil (10.7 g, 74%). 1H NMR δ (ppm)(CDCl3): 5.53 (1H, t, J=1.6 Hz), 2.69-2.51 (4H, m), 2.30-2.11 (3H, m), 1.71-1.67 (1H, m), 1.60-1.45 (2H, m), 1.05-0.99 (1H, m), 0.92-0.88 (1H, m), 0.60-0.56 (4H, m), 0.26-0.18 (4H, m).
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH:10]1[CH2:14][CH2:13][O:12][CH:11]1[O:15][CH:16]([CH3:18])[CH3:17])[C:5](OCC)=[O:6].Cl.N(CCO)CCO>C(O)C.O>[CH:16]([O:15][CH:11]1[CH:10]([CH:4]([OH:3])[CH2:5][OH:6])[CH2:14][CH2:13][O:12]1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(O)C1CCOC1OC(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCNCCO
Solvent: O
Solvent: CCO
Product: CC(C)OC1OCCC1C(O)CO
Temperature: 25 °C
Reaction time: 19 h

Procedure:
In a 2 L round bottom flask charged with 600 mL of ethanol and NaBH4 (12.55 g, 0.33 mol, 1.1 eq.) at 0° C., ethyl hydroxy-(2-isopropoxytetrahydro-3-furanyl)acetate (70 g, 0.3 mol, 1 eq.) dissolved in 400 mL of ethanol was added dropwise over 1 hour at 0° C. The mixture was allowed to warm up at room temperature and stirred for 19 hours. After cooling at 0° C., diethanolamine hydrochloride (46.7 g, 0.33 mol, 1.1 eq.) dissolved in 100 mL of water was added over 10 min. and stirred for 8 hours. The solvent was evaporated under reduced pressure to afford a clear yellow solid. After dilution with 300 mL of ethylacetate, the heterogeneous mixture was filtered over dicalite. The mixture was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:33]([C@:27]1([C:30]([N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (145 mg, 0.627 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (140 mg, 0.52 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (253 mg, 0.572 mmol) followed by triethylamine (0.156 mL, 1.12 mmol). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography on silica gel (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.15 g of desired product. MS calculated for C24H35F3N4O3: (M+H) 485; found 385.2 (M-Boc+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=O.[H-].[Na+].[CH3:13]I.CN([CH:18]=[O:19])C>C1COCC1>[CH3:2][C:3]1([CH3:13])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:18]1=[O:19]
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)Oc2ccccc21
Yield: 65 %

Procedure:
A solution of 3H-Benzofuran-2-one (4.02 g, 30 mmol) dissolved in THF (15 mL) was added cautiously to a suspension of NaH (95% dry, 1.58 g, 66 mmol) in DMF (60 mL) and THF (30 mL) under a nitrogen atmosphere, at 0° C. The mixture was stirred until gas evolution ceased, then MeI (5.6 mL, 90 mmol) was added slowly to avoid boiling over. After MeI addition was complete the reaction further stirred 1 h at room temperature then quenched by carefully pouring onto a mixture of HCl (1N) and ice. The resulting solution was extracted with ether, washed with brine, dried over MgSO4, and chromatographed on silica eluted with a gradient of 5-50% ethyl acetate/hexanes, yielding 3.16 g (65% yield) of the product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:15]Br>C(O)(=O)C>[Br:15][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2c(Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid (3.0 g, 15.9 mmol) was suspended in acetic acid (40 mL) and with vigorous stirring a solution of bromine (817 μL, 15.9 mmol) in acetic acid (10 mL) was added drop wise during 30 minutes. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying in vacuo afforded 3.74 g (88%) of 4-bromo-3-hydroxynaphthalene-2-carboxylic acid as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][C:3]=1[O:25]C.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][C:3]=1[OH:25]
Reactant: COc1cc(-n2c(C[C@@H]3CCN(C(=O)C4CC4)C3)n[nH]c2=O)ccc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)c(O)c2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round bottom flask, 4-[4-bromo-3-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.349 mmol) was dissolved in dichloromethane (3.5 mL) and cooled to 0° C. Boron tribromide (2.443 mmol) was added to the solution slowly, which was then allowed to warm to room temperature. The reaction was stirred for 1 h, and analysis by LCMS indicated complete conversion to desired product. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title product as a tan solid (110 mg, 77%). MS(ES)+ m/e 407.1, 408.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)[CH:10]=[C:9]2[C:5]=1[C:6]([CH3:14])=[N:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (400 mg, 0.928 mmol) in DMF (20 mL) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (397 mg, 1.02 mmol) followed by sodium carbonate (246 mg, 2.32 mmol) dissolved in water (4 mL) and degassed with argon for 30 min. PdCl2(PPh3)2 (65 mg, 0.092 mmol) was added and the mixture again degassed with argon for 10 min. The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (650 mg). The crude compound was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM). The product was triturated with diethyl ether (150 mL) to afford the title compound as an off white solid (270 mg, 47%). 1H NMR (DMSO-d6, 400 MHz): δ 1.498 (s, 9H), 1.560 (d, J=6.4 Hz, 6H), 2.128 (s, 3H), 2.413 (s, 3H), 2.526 (s, 3H), 3.579 (s, 8H), 4.610 (d, J=5.6 Hz, 2H), 4.760-4.824 (m, 1H), 5.907 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 7.311-7.346 (m, 2H), 7.454 (s, 1H), 7.735 (d, J=8.8 Hz, 1H), 8.463 (s, 1H), 10.991 (brs, 1H). LCMS (ES+): 614.25.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:9](=[N:10]O)[C:4]=2[CH:3]=[CH:2]1.[OH2:12]>>[S:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[C:9](=[O:12])[NH:10][CH2:8][CH2:7]1
Reactant: O
Reactant: ON=C1CCSc2sccc21
Product: O=C1NCCSc2sccc21
Reaction time: 0.33 h

Procedure:
To 300 g of polyphosphoric acid warmed at 70° C. was added 19.5 g of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one 4-oxime portionwise with stirring for 20 minutes. The mixture was stirred at 80° C. for 2.5 hours, poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude crystals were recrystallized from ethanol to give 10 g of 2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 195°-196° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([CH3:31])[C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate (300 mg, 0.710 mmol, 1.00 equiv), dichloromethane (5 mL), trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h at room temperature, concentrated under reduced pressure to yield 229 mg (crude) of N,N-dimethyl-5-phenyl-2-(piperazin-1-ylmethyl)benzamide as light yellow oil. LCMS (ESI, m/z): 324 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC#N>[O:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: NCC1CCOCC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cnc(Nc2cc(NCC3CCOCC3)ncn2)cn1
Yield: 41.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (20 mg, 0.086 mmol), 4-(aminomethyl)tetrahydropyran (18 mg, 0.17 mmol), and triethylamine (0.02 mL, 0.13 mmol) in MeCN (0.2 mL) was heated to 145° C. for 30 minutes by microwave irradiation. The mixture was cooled and solvent was removed by evaporation. The crude material was redissolved in a mixture of dichloromethane (89%), MeOH (10%), 0.88 s.g. NH3 (1%) and adsorbed onto a solvent-conditioned Trikonex silica chromatography column. Elution with the same solvent mixture gave 5-(6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile as a yellow powder (11 mg, 41%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]3=[N:36][CH:37]=[C:38]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:39]=[C:34]3[N:33]=[C:32]2[C:46]2[C:47]([NH2:52])=[N:48][CH:49]=[CH:50][CH:51]=2)=[CH:27][CH:26]=1>CC(N(C)C)=O>[NH2:52][C:47]1[C:46]([C:32]2[N:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:30][CH:29]=3)[C:35]3=[N:36][CH:37]=[C:38]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:39]=[C:34]3[N:33]=2)=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cc(-c4cccnc4)cnc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: Nc1ncccc1-c1nc2cc(-c3cccnc3)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Benzoic acid (0.85 g, 7.1 mmol) and CDI (1.14 g, 7.1 mmol) were dissolved in DMA (36 ml). The reaction mixture was stirred for 1 h. 3-(3-(4-(aminomethyl)phenyl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride was dissolved in DMA (40 ml) and the solution of benzoic acid and CDI was added over 10 min at room temperature. The reaction was stirred for two hours at room temperature and quenched by addition of water. The product N-(4-(2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide precipitated and was isolated by filtration, washed with water and ether, yielding 2.9 g (5.9 mmol, 84%) of the desired product in 98% purity. 1H NMR (DMSO-d6) 400 MHz δ: 9.15 (t, J=5.6 Hz, 1H), 9.01-9.00 (m, 1H), 8.67-8.66 (m, 1H), 8.63-8.62 (m, 1H), 8.58-8.57 (m, 1H), 8.22-8.19 (m, 1H), 8.02-8.00 (m, 1H), 7.95-7.92 (m, 2H), 7.57-7.45 (m, 8H), 7.29-7.27 (m, 1H), 7.03 (s, br, 2H), 6.45-6.42 (m, 1H), 4.59-4.58 (m, 2H) MS 498.55, [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)O
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 129.9 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (359 mg, 1.107 mmol), butyric acid (146 mg, 1.66 mmol), HATU (631 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.286 ml, 1.66 mmol) in 5.5 ml of dimethylformamide in a 20 ml round-bottomed flask, equipped with a magnetic bar, is stirred for 8 hours at 60° C. and then left overnight at room temperature. The reaction medium is extracted with ethyl acetate and washed with water and then with 0.1 N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained (567 mg of pale yellow solid) is purified by chromatography on a 40 g Biotage silica cartridge, eluting with a 9/1 toluene/isopropanol mixture. After evaporating off the solvent, 239 mg of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester are obtained (white solid) in a yield of 55%.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C(=O)c1cnc2c(O)cccc2c1Cl
Temperature: 25 °C

Procedure:
A solution of 3-isobutyryl-4-chloro-8-methoxy-quinoline (21.1 g, 80 mmol) in dichloromethane (320 ml) was cooled to -10° and boron tribromide (60.13 g, 240 mmol) added dropwise under nitrogen. The solution was allowed to warm to room temperature, and after 16 hours was poured onto crushed ice (500 g). The layers were separated, and the aqueous layer further extracted with dichloromethane. The combined extracts were washed with brine, dried and evaporated to a yellow solid (29.75 g). This complex of 3-isobutyryl-4-chloro-8-hydroxyquinoline was used without further purification.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[Br:16]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:16][C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:14][CH3:15])=[O:13]
Reactant: C#CCCCCCCCCCC(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCC#CBr
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.9 %

Procedure:
To a mechanically stirred solution of ester 4 (37 g, 176 mmol) in 700 mL of acetone under nitrogen was added N-bromosuccinimide (34.4 g, 194 mmol) followed by silver nitrate (2.7 g, 18 mmol). The reaction mixture was allowed to stir at room temperature in the absence of light for 21 h. The thick, pale yellow reaction mixture was filtered through a sintered glass funnel, concentrated in vacuo to one third volume, and diluted with 500 mL of water. This was extracted with 4×250 mL of hexanes, and the combined organic layers were washed with 100 mL of brine, dried over sodium sulfate, concentrated in vacuo, and vacuum dried to give bromoacetylene 5 (47.81 g, 94%) as a yellow oil:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)[CH3:2].[CH2:14](NO)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC2[N:31]([OH:32])N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:6](=[O:8])[NH:31][O:32][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C(CC(C)C)C(=O)O
Reactant: ONCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)C(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
Intermediate (3a) (40.3 g, 214 mmol, 1.0 eq) was dissolved into 800 mL DCM and 900 mL THF and the solution was cooled to 0° C. To this was added benzyl hydroxylamine (34.2 g, 214 mmol, 1.0 eq) followed by HOBt (28.9 g, 214 mmol, 1.0 eq). The mixture was stirred for 5 minutes, then DCC (44.1 g, 214 mmol, 1.0 eq) was added, followed by triethylamine (33.4 mL, 240 mmol, 1.1 eq). The mixture was warmed to room temperature and stirred overnight. The solid was filtered and the filtrate was concentrated. The material was redissolved in 1000 mL EtOAc and washed with 500 mL 1N HCl, 600 mL saturated aq. bicarbonate, dried over MgSO4, filtered. and evaporated to yield intermediate (3b) (59.3 g) as a semisolid. MS m/z: [M+H+] calcd for C16H23NO4 294.2. found 294.2.