Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:5]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH2:3][C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:5]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](CC#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](CC#N)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-cyanomethyl-cyclopentyl)-amide (126 mg, 0.23 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.7 ml, 9.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.2 ml) and ethylenediamine (0.93 ml, 13.8 mmol) was added. The yellow solution was stirred at room temperature for 1.25 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 75 mg (74%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-cyanomethyl-cyclopentyl)-amide as a light yellow powder. MS: (M+H)+=418; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.61 (br. s., 1H), 9.09 (s, 1H), 8.40-8.49 (m, 2H), 8.18 (d, J=7.2 Hz, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.24 (td, J=9.2, 2.1 Hz, 1H), 4.29-4.45 (m, 1H), 4.15 (s, 3H), 2.66 (d, J=6.4 Hz, 2H), 2.34-2.43 (m, 1H), 2.23-2.34 (m, 1H), 2.11-2.23 (m, 1H), 1.85-2.00 (m, 1H), 1.46-1.74 (m, 2H), 1.28-1.41 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[OH:16][N:15]=[C:9]([C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccccn1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl picolinoylacetate (0.500 g, 2.6 mmol) in acetic acid (0.5 mL) was added a solution of sodium nitrite (0.238 g, 3.4 mmol) in water (0.5 mL), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (0.5 mL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353 g, 1.6 mmol, 61%) as a white solid. 1H NMR (DMSO) δ 1.17 (3H, t), 4.22 (2H, q), 7.74 (1H, m), 8.04-8.11 (2H, m), 8.74 (1H, m), 12.87 (1H, s). LCMS (2) Rt: 1.09 min; m/z (ES+) 223.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].CN(C=O)C.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]([CH3:39])[N:27]=[C:28]2[C:37]=1[C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:30]=[C:29]2[NH2:38]>O>[NH2:38][C:29]1[C:28]2=[N:27][N:26]([CH3:39])[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:37]2[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Potassium phthalimide (4.90 mg, 26.4 mmol), sodium iodide (495 mg, 3.30 mmol), and DMF (22 mL) were added to 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (4.00 g, 13.2 mmol, prepared as described in Parts A-F of Examples 454-489), and the reaction was heated at 90° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water (100 mL) was added and a precipitate formed and was isolated by filtration to yield 3.7 g of 2-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione that was used in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[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.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=[CH:39][N:38]=2)[CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:41]3[CH:40]=[CH:39][N:38]=[C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)[CH:42]=3)[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]=2[C:6]([CH3:14])=[N:7]1)([CH3:13])[CH3:12]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccnc(N3CCN(C)CC3)c2)cc2c1c(C)nn2C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (85 mg, 0.19 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (72.9 mg, 0.24 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (7.6 mg, 0.0093 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (46.6 mg, 0.55 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 110° C. for 20 min. The mixture was evaporated, DCM was added and the contents purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes. The contents were sonicated and solids that precipitated were filtered. Acetonitrile was added, the solids were triturated, and again filtered. The collected solid was then suspended in DMF along with some water and then allowed to sit at room temperature overnight. Solids that precipitated were filtered, washed with DCM, and dried to afford the title compound as a light grey solid (34 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H) 8.45 (t, J=4.93 Hz, 1H) 8.19 (d, J=5.31 Hz, 1H) 8.06-8.09 (m, 1H) 7.40 (s, 1H) 7.17 (s, 1H) 7.08 (d, J=5.05 Hz, 1H) 5.91 (s, 1H) 5.11 (quin, J=6.57 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.55-3.62 (m, 4H) 2.53-2.57 (m, 2H) 2.41-2.46 (m, 7H) 2.24 (s, 3H) 2.13 (s, 3H) 1.53-1.61 (m, 2H) 1.47 (s, 3H) 1.46 (s, 3H) 0.93 (t, J=7.33 Hz, 3H); LC-MS (ES) m/z=459.2
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15]C)=[O:14])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>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.O1CCOCC1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=[C:2]2[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(Br)c2cccc(F)c2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(F)cc2)c2cccc(F)c2n1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl 4-bromo-8-fluoroquinoline-2-carboxylate (7-3, 100.0 mg, 0.352 mmol), 4-Fluorophenylboronic acid (59.1 g, 0.422 mmol), Tetrakis (20.3 mg, 0.0180 mmol), and Na2CO3 (0.704 ml, 0.704 mmol) were added into 1,4-Dioxane (1.0 mL) in a microwave reaction vessel. The mixture was irradiated with microwave at 100° C. for 30 min. Cooled to room temperature, aqueous Sodium Hydrogen Carbonate (saturate, 2.0 mL) was added and extracted with Ethyl Acetate (2×10.0 mL). The combined organic fractions were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4, 100.0 mg, 100.0% crude). LRMS m/z (M+H)+ 286.2 found, 286.2 required.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+].O>CCO>[O:7]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: BrCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Phenol (3.10 g, 33 mmol), 1,7-dibromoheptane (7.74 g, 30 mmol) and NaOH (1.34 g, 33 mmol) were refluxed in EtOH (40 mL) for 30 h. After cooling to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), and the mixture was dried over Na2SO4. After evaporation of solvent, the residue was purified by Kugelrohr distillation to give 7-phenoxyheptyl bromide (2.46 g, 30%), bp 126-130° C./0.10 torr, 1H-NMR: 1.2-1.9 (m, 10H), 3.36 (t, 2H), 3.91 (t, 2H), 6.7-7.2 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:60])[N:7]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([C:45]([N:47]2[CH2:51][C:50](=[CH2:52])[CH2:49][C@H:48]2[C:53](OC)=[O:54])=[O:46])=[CH:39][C:38]=1[N+:57]([O-:59])=[O:58])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([N:21]2[CH2:25][C:24](=[CH2:26])[CH2:23][C@H:22]2[C:27](OC)=[O:28])=[O:20])=[CH:13][C:12]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:60])[N:7]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([C:45]([N:47]2[CH2:51][C:50](=[CH2:52])[CH2:49][C@H:48]2[CH:53]=[O:54])=[O:46])=[CH:39][C:38]=1[N+:57]([O-:59])=[O:58])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([N:21]2[CH2:25][C:24](=[CH2:26])[CH2:23][C@H:22]2[CH:27]=[O:28])=[O:20])=[CH:13][C:12]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)c2cc([N+](=O)[O-])c(OCCN(CCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4C(=O)OC)cc3[N+](=O)[O-])C(=O)OC(C)(C)C)cc2OC)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C1C[C@@H](C=O)N(C(=O)c2cc([N+](=O)[O-])c(OCCN(CCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4C=O)cc3[N+](=O)[O-])C(=O)OC(C)(C)C)cc2OC)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
To a vigorously stirred solution of bis{2-[5-methoxy-2-nitro-4-[(S)-4-methylene-2-methoxycarbonyl-1-pyrrolidinylcarbonyl]phenyloxy]-ethyl}-carbamic acid tert-butyl ester 12 (100 mg, 0.12 mmol) in anhydrous toluene (2.4 mL) was added dropwise solution of DIBAL-H (480 μL of a 1M solution in toluene) at −78° C. under argon atmosphere. After the mixture was stirred for an additional 45 min, excess reagent was decomposed by addition of five drops of methanol followed by 5% HCl (4 mL). The resulting mixture was allowed to warm to 0° C. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (3×3 mL). Combined organic layers were washed with brine, dried (MgSO4) and concentrated. Purification of the residue by flash chromatography (silica gel, 95:5 CHCl3/MeOH) yielded bis{2-[5-methoxy-2-nitro-4-[(S)-4-methylene-2-formyl-1-pyrrolidinylcarbonyl]phenyloxy]-ethyl}-carbamic acid tert-butyl ester 13 as light yellow oil (84 mg, 91%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[OH-].[Na+]>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1Cl
Yield: 87 %

Procedure:
To 0.97 g (~0.01 mole) of freshly prepared N-methylaniline (b.p. 196° C.) is added 1.94 g (~0.01 mole) of 2-chlorobenzenesulfonyl chloride (98 w/w %). The mixture is stirred until it becomes hot, and then ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. 2-chloro-N-methylbenzenesulfonanilide is formed as a viscous yellow liquid. It is washed with water several times until the wash water is neutral to litmus paper, and the viscous yellow liquid extracted with ether. The ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of a yellow oil is 2.2 g (87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:25])[CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 195.4 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)azepane-1-carboxylate (1.44 g, 4.35 mmol) in tetrahydrofuran (22 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (621 mg, 2.17 mmol) in 4 portions over 15 min. The mixture was allowed to stir (−20° C.) for 4 h. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 5% aqueous K2CO3 (25 mL), brine, dried (Na2SO4) and evaporated to provide 1.74 g (98%) of the desired product, which contained trace impurities. ES-MS m/z 411.91 [M+H]+, HPLC RT (min) 2.92.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)([C:20]1[NH:21]C=CN=1)=O.CN.C(Cl)Cl>CN(C=O)C.C1COCC1.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:14]=1[C:15]([NH:21][CH3:20])=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cnccc1NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
The acid, 4-tert-Butoxycarbonylamino-nicotinic acid (1.0 g, 4.20 mmol) was suspended in dry DMF (50 mL) followed by carbonyl-diimidazole (CDI, 1.36 g, 8.40 mmol). The mixture was heated to 60° C. for 1 h, then cooled. Methyl amine in THF was added to the solution followed by evaporation of the mixture. The residue was dissolved in water (20 mL)/chloroform (50 mL) and shaken then the layers separated. The aqueous layer was extracted further with chloroform (3×50 mL) and the combined organic extracts dried (MgSO4) and evaporated to give a yellow oily solid. Silica gel chromatography (CH2Cl2, 0-15% MeOH gradient) gave the desired product, (3-(N-methylaminocarbonyl)-pyridin-4-yl)-carbamic acid tert-butyl ester, as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N+:6]=1[O-])=[O:4].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(C)ccc[n+]1[O-]
Product: COC(=O)c1nc(Cl)ccc1C
Yield: 37 %

Procedure:
A solution of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (2 g, 6.0 mmol) in POCl3(5 mL) was stirred at 100° C. for 3 hours. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=1:1) to give the product of methyl 6-chloro-3-methylpicolinate (380 mg, yield: 37%). 1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 3.96 (s, 3H), 2.56 (s, 3H). MS (M+H)+: 186/188.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1CCNCC1
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: COc1cc(C(=O)N2CCN(C)CC2)ccc1N
Reaction time: 18 h
Yield: 31.2 %

Procedure:
HATU (1179 mg, 3.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (461 mg, 2.76 mmol), DIPEA (1.24 mL, 7.12 mmol) and 1-methylpiperazine (230 mg, 2.30 mmol) in DMF (12 mL) and the reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by elution through an SCX-2 column to afford the title compound as brown oil (179 mg, 31%).
Reaction SMILES: CN(C=O)C.O.Br[C:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[N:10]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>O.C(OCC)(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[N:10]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:9]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(Br)cn(-c4ccncc4)c3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.6 %

Procedure:
DMF/water (4:1, 2 mL) was added to a mixture of tert-butyl 4-(3-bromo-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (29 mg, 0.0636 mmol), potassium carbonate (18 mg, 0.13 mmol) and 4-methoxyphenylboronic acid (11 mg, 0.070 mmol) and the dissolved gas was removed. After adding Pd(dppf) Cl2 (10.4 mg, 0.013 mmol), the mixture was stirred at room temperature for 14 hours. After adding ethyl acetate and water, the mixture was filtered using a diatomite pad. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4 1:1). The target compound (31 mg) was obtained as white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[C:17](\[F:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[C:17](\[F:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 27.5 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A mixture of ethyl (2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (720 mg), cyclopentanone (188 mg), sodium triacetoxyborohydride (1.18 g) and Et3N (0.52 ml) in CHCl3 (20 ml) was stirred at 25-30° C. for 15 hours. The 10% K2CO3 solution (20 ml) was added to a reaction mixture and stirred at ambient temperature for 30 minutes and extracted with CH2Cl2 and washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with CHCl3-MeOH (96:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (710 mg).
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:9]2=[N:10][O:11][N:12]=[C:8]2[CH2:7][CH2:6]1)C.[OH:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH2:25])=[NH:24])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C>[N:10]1[O:11][N:12]=[C:8]2[CH2:7][CH2:6][C:5]3[C:13](=[N:24][C:23]([NH:22][C:18]4[CH:17]=[C:16]([OH:15])[CH:21]=[CH:20][CH:19]=4)=[N:25][CH:4]=3)[C:9]=12
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: CN(C)C=C1CCc2nonc2C1=O
Solvent: CN(C)C=O
Product: Oc1cccc(Nc2ncc3c(n2)-c2nonc2CC3)c1

Procedure:
The DMF solution of 5-dimethylaminomethylene-6,7-dihydro-5 H-benzo[1,2,5]oxadiazol-4-one 0.1 g (0.00052 mol) and 3 equivalents of N-(3-hydroxy-phenyl)-guanidine was stirred at 110° C. for overnight, the final product was purified by directly injecting the DMF reaction solution into prep HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:19]2[N:18]=[C:17]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]4[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)[CH2:13][CH2:12]3)[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=2)=[CH:29][CH:30]=1
Reactant: Cc1cc(N2CCC(N)CC2)c(C)cn1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)c(C)cn1
Temperature: 150 °C
Yield: 30 %

Procedure:
To a mixture of 2′,5′-dimethyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-4-ylamine (143 mg, 0.48 mmol), 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (99 mg, 0.48 mmol), finely milled potassium carbonate (100 mg, 0.72 mmol) in dioxane (2 mL) was added under an argon atmosphere palladium(II) acetate (5 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.05 mmol) and the reaction mixture was heated at 150° C. for 30 minutes. Concentration and purification by chromatography (SiO2, n-heptane/ethyl acetate/(ethyl acetate/triethylamine=95:5)=50:50:0 to 0:80:20) afforded the title compound (67 mg, 30%) as a light brown foam.