Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added dimethylamine hydrochloride (24.02 mg, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (21 mg, 19% yield). m.p.=99.2° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.04 (m, 3 H) 2.12-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 2.94 (s, 6 H) 3.14-3.23 (m, 4 H) 3.35-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=1.77 Hz, 1 H) 7.29 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.52 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:34]=[N:33][C:32]5[NH:31][C:30](=[O:35])[CH2:29][O:28][C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:34]=[N:33][C:32]5[NH:31][C:30](=[O:35])[CH2:29][O:28][C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (17.1 mg, 0.027 mmol) in THF (1.1 mL) and methanol (1.1 mL) was added 1N NaOH solution (0.8 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H28ClN4O5S: 615.2; found: 615.2. 1H NMR (400 MHz, CD3OD) δ 8.74 (d, J=4.8 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.91 (dd, J=5.2, 1.6 Hz, 1H), 7.71-7.68 (m, 1H), 7.62-7.59 (m, 3H), 5.28 (s, 1H), 4.72 (s, 2H), 2.63 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.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.[CH3:60][O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[CH2:68][NH2:69]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][CH2:68][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=3[O:61][CH3:60])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: COc1ccccc1CN
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 1-[2-(Methyloxy)phenyl]methanamine (65.6 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (200 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:13][C@H:12]3[CH2:23][CH3:24])=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH:29]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)([CH3:31])[CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH2:23]([C@H:12]1[C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:28]=[C:2]([C:35]4[CH:34]=[N:33][N:32]([CH:29]([CH3:31])[CH3:30])[CH:36]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:25]([NH2:27])=[O:26])[CH2:16][CH2:15][N:14]([C:17](=[O:22])[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:13]1)[CH3:24]
Reactant: CC[C@@H]1CN(C(=O)C(C)(C)O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H]1CN(C(=O)C(C)(C)O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C(C)C)c3)cc12
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a vial charged with 6-bromo-4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)-piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.88 mg, 0.088 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (3.61 mg, 4.42 μmol) were added 1,4-dioxane (295 μl) and a 2M solution of potassium phosphate (66.3 μl, 0.133 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation, yielding 4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (14.6 mg, 0.030 mmol, 68.6% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.10 (s, 1H), 7.83 (s, 1H), 7.75-7.72 (m, 2H), 6.92 (d, J=1.5 Hz, 1H), 4.65-4.50 (m, 2H), 4.32 (s, 2H), 4.15 (br. s., 1H), 2.97 (d, J=12.4 Hz, 1H), 2.36 (d, J=11.4 Hz, 1H), 1.79 (br. s., 1H), 1.70-1.61 (m, 2H), 1.57 (d, J=6.4 Hz, 6H), 1.49 (s, 6H), 1.41-1.25 (m, 1H), 1.01 (t, J=7.4 Hz, 3H). HPLC (Method F) Rt: 1.966 min. LCMS (Method K) m/z 482.29 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20]C)=O)[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C.C(#N)C>[NH:23]([C:18]([C:16]1[N:17]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][CH:15]=1)=[O:20])[NH2:24]
Reactant: COC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Reactant: NN
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The methyl 6-(benzyloxycarbonylamino)picolinate from step 1 was dissolved in ethanol (0.5 M), and hydrazine hydrate (15 mL, 310 mmol, 5.0 eq) was added. The solution was heated to reflux and stirred for 2 hours, then cooled to room temperature. The solvent was removed under reduced pressure to provide a yellow solid, which was suspended in acetonitrile, filtered, and the solid washed with acetonitrile to yield benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (17.5 g) as a white solid. The filtrate was concentrated and the precipitated solid filtered off and washed with acetonitrile to provide more benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate. A total of 17.5 g of pure material was obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:21]([CH:23]([NH2:48])[CH:24]([CH2:28][C:29]1([C:34](=[O:47])[NH:35][C@H:36]2[CH2:41][CH2:40][C@@H:39]([C:42]([O:44]CC)=[O:43])[CH2:38][CH2:37]2)[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:25]([OH:27])=[O:26])=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:3])[CH3:2]>[OH-].[Na+]>[C:1]([NH:4][C@H:5]([C:21]([CH:23]([NH2:48])[CH:24]([CH2:28][C:29]1([C:34](=[O:47])[NH:35][C@H:36]2[CH2:41][CH2:40][C@@H:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]2)[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:25]([OH:27])=[O:26])=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)O)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)C(N)C(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Reaction time: 8 h
Yield: 96.9 %

Procedure:
The ethyl ester from Example 39 (404 mg, 0.600 mmol) was dissolved in 2M sodium hydroxide solution (10 ml), and the resulting solution was kept at room temperature overnight. The reaction mixture was diluted to 30 ml and extracted with diethyl ether. The aqueous phase was acidified to pH 1 with 2M hydrochloric acid and extracted with ethyl acetate (3×25 ml). The organic phase was dried (MgSO4) and evaporated to afford the title compound (375 mg, 97%) as a white foam. Found: C,58.30; H,7.24; N,8.20. C33H48N4O9. (0.25 CH2Cl2, 1.25 H2O) requires C,58.00; H,7.17; N,8.14%.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][N:2]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.[I-].[K+]>CC(C)=O>[CH3:11][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nnc2sccc12
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc2sccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a solution of 3H-thiopheno[2,3-d]1,2,3-triazin-4-one (80 mg, 0.522 mmol) in acetone (50 mL) was added sequentially potassium carbonate (144 mg, 1.04 mmol), iodomethane (0.04 mL, 0.627 mmol) and potassium iodide (catalytic) at rt and the mixture was stirred at rt for 3 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure, diluted with ice cold water and stirred for 10 min. The solution was extracted with chloroform (4×75 mL) and the combined CHCl3 layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as an off-white solid (50 mg, 57%), mp 104-108° C. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (1H, d, J=5.6 Hz), 7.64 (1H, d, J=5.6 Hz), 3.95 (3H, s); 13C NMR (100 MHz, CDCl3): δ 159.4, 153.9, 130.7, 125.6, 121.7, 37.3.
Reaction SMILES: BrC1C=CC(OC)=CC=1CC[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH2:20](O)[CH2:21][OH:22]>>[C:14]1([CH:12]2[O:13][CH2:20][CH2:21][O:22]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCO
Reactant: COc1ccc(Br)c(CCC(=O)c2ccccc2)c1
Product: c1ccc(C2OCCO2)cc1

Procedure:
The product of step 2 is reacted with ethylene glycol to produce 2-[2-(2-bromo-5-methoxyphenyl)-ethyl]-2-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane;
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:33]2=[O:44])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:33]2=[O:44])[S:27][C:28]=1[C:29]([NH:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[O:31]
Reactant: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((tetrahydro-2H-pyran-2-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 174-175° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.51-8.40 (m, 2H), 7.61-7.59 (m, 1H), 7.20-7.14 (m, 1H), 6.58 (br s, 1H), 4.53 (s, 2H), 4.06-3.86 (m, 3H), 3.74-3.58 (m, 2H), 3.44-3.29 (m, 3H), 3.17-3.09 (m, 1H), 2.52 (s, 3H), 1.79-1.74 (m, 1H), 1.51-1.32 (m, 4H), 1.27-1.14 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.4, 149.2, 148.7, 135.5, 134.1, 123.5, 116.7, 76.6, 68.2, 49.0, 44.0, 42.2, 41.2, 28.9, 25.6, 22.8, 17.2; MS (ES+) m/z 416.3 (M+1).
Reaction SMILES: S([NH:11][C:12]([NH:14][C:15]1[N:37]=[C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:17]2[N:16]=1)=[O:13])(C1C=CC(C)=CC=1)(=O)=O.[CH2:38](N)[CH3:39].CCN(CC)CC>C1COCC1.CN(C=O)C>[CH2:38]([NH:11][C:12]([NH:14][C:15]1[N:37]=[C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:17]2[N:16]=1)=[O:13])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)Nc2nc3cc(-c4cccnc4)cc(NC4CCN(C)CC4)n3n2)cc1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(NC3CCN(C)CC3)n2n1

Procedure:
The product of Step 2 (312 mg, 0.60 mol) and ethyl amine (3 mL of a 2 M solution in THF) in DMF (2 mL) was microwaved at 100° C. for 1 h. The homogeneous solution was pre-adsorbed onto SiO2. Silica gel chromatography (5% NEt3/0-5% MeOH/EtOAc) gave an oil which was triturated with EtOAc/hexane to afford the target compound 1-ethyl-3-[5-(1-methyl-piperidin-4-ylamino)-7-pyridin-3-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea. MS m/z 395 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C(Cl)Cl.S(Cl)(Cl)=O.[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[N:33]3[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C(O)c3ccc4c(cnn4C)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1ncc2cc(C(c3ccc4c(cnn4C)c3)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A round bottom flask was charged with bis(1-methyl-1H-indazol-5-yl)methanol (50 mg, 0.17 mmol) and CH2Cl2 (5 mL). Thionyl chloride (25 μL, 342 mmol) was added, resulting in a cloudy solution. After 15 min the solution become a clear pink solution and was stirred at room temperature for 48 h. The solution was concentrated under reduced pressure. Acetonitrile was added and the solution was concentrated two times. Acetonitrile (7 mL) and tert-butyl piperazine-1-carboxylate (60 mg, 0.32 mmol) was added and the solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and purified by silica chromatography (100% CH2Cl2 to 3% MeOH in CH2Cl2) yielding tert-butyl 4-(bis(1-methyl-1H-indazol-5-yl)methyl)piperazine-1-carboxylate (53 mg, 56%) as a light brown oil. 1H NMR 400 MHz (CDCl3) δ 7.97-7.89 (m, 2H), 7.79 (s, 2H), 7.54 (dd, J=8.8, 1.5 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 4.49 (s, 1H), 4.03 (s, 6H), 3.47 (s, 4H), 2.41 (s, 4H), 1.45 (s, 9H). LCMS (ESI, m/z): 483 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:13]([CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[F:9].Cl[C:31]1[C:32]2[CH:39]([CH2:40][CH3:41])[C:38](=[O:42])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CCN(C(C)C)C(C)C.CC(O)C>O>[F:29][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([CH:23]3[CH2:24][CH2:25][N:26]([C:31]4[C:32]5[CH:39]([CH2:40][CH3:41])[C:38](=[O:42])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:27][CH2:28]3)[N:13]([CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCC1C(=O)Nc2ncnc(Cl)c21
Reactant: CN1CCCC[C@@H]1Cn1cc(-c2ccc(F)c(C(F)F)c2)nc1C1CCNCC1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(C(F)F)c5)cn4C[C@H]4CCCCN4C)CC3)c21
Yield: 5.4 %

Procedure:
Combine (R)-2-((4-(3-(difluoromethyl)-4-fluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)methyl)-1-methylpiperidine (0.8 g, 0.0018 mol, 1.0 eq); 4-chloro-5-ethyl-5,7 dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.425 g, 0.00216 mol, 1.2 eq); DIPEA (2.3 mL, 0.0126 mol, 7.0 eq) and IPA (15 mL) in a pressure tube and heat at 120° C. overnight under sealed condition. Cool the reaction mass and dilute with water (25 mL). Extract in EA (2×50 mL) and wash the organic layer with brine (2×50 mL). Dry over anhydrous sodium sulfate and concentrate the crude compound. Filter the crude product through a short silica pad (100-200 mesh) using 0-8% MeOH-DCM). LCMS of concentrated crude product shows 70% of the desired product (m/z=568 [M+H]). Purify through reverse phase preparative HPLC to get 0.055 g of the title compound. MS (ES+): m/z=568 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([N:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[CH2:39][CH2:40]CCl)=[O:37])[CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[Na+]>ClCCl.O>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([N:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[CH2:39][CH2:40][CH2:6][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:12][CH2:13]2)=[O:37])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)CC1
Reactant: CC(=O)N1CCC(C(=O)N(CCCCl)c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cn3cncn3)CC2)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidine (48 mg, 0.18 mmol) in dry dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled of under reduced pressure, and the residue was dissolved in methanol (1 mL). The solvent was distilled off under reduced pressure, and the residue was dissolved in dry acetonitrile (1.5 mL). To the solution were added 1-acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide (50 mg, 0.14 mmol), potassium carbonate (77 mg, 0.56 mmol) and potassium iodide (23 mg, 0.14 mmol), and the mixture was stirred at 80° C. for 5 hours. The mixture was cooled to room temperature, and to the mixture was added water. The mixture was saturated with sodium chloride, and extracted three times with ethyl acetate (2 mL). The extracts were combined and concentrated under reduced pressure. The concentrate was purified by using HPLC to give the titled compound as a colorless oily substance (49.1 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:20][N+:17]([O-:19])=[O:18])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(C=C[N+](=O)[O-])cc(C)c1O
Temperature: 45 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
Commercially available 3,5-dimethyl-4-hydroxybenzaldehyde (1.50 g, 10.0 mmol), ammonium acetate (850 mg, 11.0 mmol), and nitromethane (7.00 mL) were mixed, and the mixture was stirred at 45° C. for 5 hours. Then, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2,6-dimethyl-4-(2-nitrovinyl)phenol (1.82 g, yield 94%). This compound (1.82 g, 9.42 mmol) was dissolved in THF (60.0 mL), then lithium aluminum hydride (1.14 g, 30.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, sodium sulfate decahydrate (9.67 g, 30.0 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The resulting precipitate was filtered out, and the filtrate was concentrated under reduced pressure. A hydrogen chloride-ethyl acetate solution (4.00 mol/L, 10.0 mL, 40.0 mmol) was added thereto, and precipitated crystals were collected by filtration to give 2,6-dimethyl-4-(2-aminoethyl)phenol hydrochloride (477 mg, yield 25%).
Reaction SMILES: [OH-].[Na+].O.O.[I:5][C:6]1[CH:7]=[C:8]([CH:15]=[C:16]([I:19])[C:17]=1[OH:18])[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11].S([O-])([O-])(=O)=O.[Cu+2:25]>O>[Cu:25].[I:5][C:6]1[CH:7]=[C:8]([CH:15]=[C:16]([I:19])[C:17]=1[OH:18])[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11]
Reactant: [Cu+2]
Agent: N[C@@H](Cc1cc(I)c(O)c(I)c1)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Cu]
Temperature: 22.5 °C

Procedure:
RBF was charged with 1200 ml of water and 15.01 gms of sodium hydroxide at 20-25° C. and stirred to get a clear solution. 100 gms of 3,5-Diiodotyrosine dihydrate was added and to the above mixture and stirred for an hour to get a clear solution. Copper sulphate solution (35.94 gms dissolved in 225 ml of water at 40° C.) was then added into the reaction mixture over a period of 1 hr and maintained at 20-25° C. for 1 hr. The resultant reaction mixture is filtered and washed with 1500 ml of DM water and dried under vacuum at 55-60° C. to get 95 gms of 3,5-Diiodo L-Tyrosine copper complex. The purity of obtained complex is NLT 97% with yield of 93-98%.