Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]4[NH2:28])[CH:18]=[C:17]([C:29]#[N:30])[C:12]=3[C:13](OC)=[O:14])[CH:8]=2)[CH:3]=[N:2]1>CO.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[C:13](=[O:14])[NH:30][CH2:29][C:17]=4[CH:18]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]4[NH2:28])[N:20]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc2cn[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCCC[C@H]1Nc1cc2c(c(Nc3ccc4cn[nH]c4c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of methyl 2-(1H-indazol-6-ylamino)-6-((1R,2S)-2-aminocyclohexylamino)-4-cyanonicotinate (88 mg, 218 mmol) in MeOH (2 mL) was added palladium on carbon, and the resulting mixture was stirred at room temperature overnight under H2 atmosphere. The mixture was subsequently filtered to remove the catalyst and the filtrate was evaporated. The residue was diluted with saturated aq NaHCO3 and MeOH, and the mixture was stirred at RT for 30 min. The resulting suspension was filtered and the precipitate was washed with EtOAc and dried to give the title compound as a white solid (15 mg, 18.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.74 (m, 8H), 3.13 (br s, 1H), 3.94-4.07 (m, 1H), 4.21 (s, 2H), 6.02-6.14 (m, 1H), 6.70 (br s, 1H), 7.13 (d, J=8.30 Hz, 1H), 7.63 (d, J=8.30 Hz, 1H), 7.94 (d, J=2.93 Hz, 2H), 8.23 (s, 1H), 9.08 (s, 1H), 12.84 (br s, 1H). [M+H] calc'd for C20H23N7O, 378. found, 378.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13](Cl)[N:12]=1.C(N(CC)CC)C>C(#N)C>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Phenethylamine (7.0 g, 58.4 mmol) was added to a stirred solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (14.5 g, 53.1 mmol) (preparation 5) and triethylamine (21 g, 212.5 mmol) in acetonitrile (200 ml). The reaction mixture was stirred for 3 hr at room temperature and then more phenethylamine (1 g, 8.3 mmol) was added. The reaction mixture was stirred for a further 1 hr and then the solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether (500 ml) and water (250 ml). The diethyl ether layer was washed with more water (300 ml). The solvent was removed from the organic phase under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with diethyl ether to give the title compound (17.9 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@:14]([OH:16])([CH3:15])[C@@H:13]([CH3:17])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[OH:16][C@@:14]1([CH3:15])[C@@H:13]([CH3:17])[CH2:12][NH:11][CH2:10][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of benzyl (3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate (100 mg, 0.265 mmol) in MeOH (5.0 mL), 10 wt % Pd on carbon (33 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 h. The reaction was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification (60 mg, 92%). LCMS calc. for C12H25N2O3 (M+H)+: m/z=245.2. found 245.0.
Reaction SMILES: [C:1]([N:5]([C:13]([C:15]([O:17]CC)=O)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])([CH3:4])([CH3:3])[CH3:2]>CCOCC>[C:1]([N:5]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12][C:15](=[O:17])[C:13]1=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)N(c1ccccc1N)C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)n1c(=O)c(=O)[nH]c2ccccc21
Temperature: 25 °C

Procedure:
The neat crystals of N-tert-butyl-N-ethoxalyl-o-phenylene diamine (88 g) were heated to 100° C. for 4 h. The crude product hereby deposited from the melt as crystals. After cooling to ambient temperature the solid taken in ether and the product was filtered off as white crystals, m.p. >300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[CH:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.84 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (328 mg, 1.27 mmol) and K3PO4 (445 mg, 0.706 mmol), in DMF (6 mL)-water (0.6 mL) was added dichlorobis(triphenylphosphine) palladium (II) (30 mg, 0.042 mmol). The reaction mixture was heated at 90° C. for 95 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-4-carboxamide. 1H NMR (TFA salt, CD3OD) d (ppm): 7.57-7.78 (m, 5H), 7.4 (dd, 1H), 7.25 (s, 1H), 6.92-7.2 (m, 4H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.83 (m, 6H), 2.5 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][N:15]([C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:42]([C:45]1[CH:55]=[CH:54][C:48]([C:49]([O:51]CC)=[O:50])=[CH:47][CH:46]=1)=[C:43]=[O:44].O>C1(C)C=CC=CC=1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:43]([NH:42][C:45]2[CH:55]=[CH:54][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=2)=[O:44])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of 300 mg of tert-butyl {[4-(3-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 3.0 mL of toluene was added 0.136 mL of triethylamine and 149 mg of ethyl 4-isocyanatobenzoate at room temperature, followed by stirring at 100° C. for 2 days. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 8 mL of THF, 4 mL of methanol, and 4 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 24 hours. The reaction mixture was neutralized by addition of 4.1 mL of 1 M hydrochloric acid, then concentrated under reduced pressure, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 356 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}amino)benzoic acid as a colorless foamy substance. ESI+: 626
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C>[CH2:36]([O:35][CH2:34][CH2:33][O:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](O)[C@H]2OC(C)(C)O[C@H]21
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](OCCOCc2ccccc2)[C@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)carbamate (3.0 g, 10.8 mmol) in dry DMF (30 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 530 mg, 13.0 mmol). After stirring for 30 min at 0° C., 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (3.3 g, 10.8 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (30 mL). To the mixture was extracted 3×30 mL of n-hexane. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIc was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: [ClH:1].[O:2]([NH2:4])[CH3:3].[C:5]1([C:11]#[C:12][C:13]2[CH:14]=[C:15]([C:19](=O)[CH3:20])[CH:16]=[N:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[CH3:3][O:2][N:4]=[C:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:12]#[C:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:14]=1)[CH3:20]
Reactant: CON
Reactant: CC(=O)c1cncc(C#Cc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=C(C)c1cncc(C#Cc2ccccc2)c1
Yield: 38.2 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using methoxylamine hydrochloride (700 mg, 8.4 mmol), 1-(5-phenylethynylpyridin-3-yl)-ethanone, (prepared as described in EXAMPLE 84), (230 mg, 1.05 mmol) and potassium carbonate (720 mg, 5.24 mmol) to give the title compound (115 mg, 38%).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=O)[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>CO>[CH2:1]=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=[N:24][OH:25])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: C=C1c2cnccc2CC(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2cnccc2CC(=NO)c2ccccc21

Procedure:
A mixture of the ketone from Step E (6.2 g.), anhydrous sodium acetate (3.1 g.), hydroxylamine hydrochloride (2.48 g.) and CH3OH (130 ml.) is heated under reflux for 24 hours. The solvent is removed in vacuo, water (100 ml.) is added to the residue and the resulting yellow-orange solid is collected and dried, 6.4 g., m.p. 183°-205° C. Recrystallization from toluene provides material with m.p. 218.5°-221° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:12]=3[Cl:22])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[N:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:16]1[CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=[C:12]([Cl:22])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[N:25]=3)=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Cc1cc(N)nc(C)n1
Reactant: CS(=O)(=O)c1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(S(C)(=O)=O)cc4Cl)cc23)nc(C)n1
Yield: 59.4 %

Procedure:
A suspension of 4-chloro-2-(2,6-dichloro-4-methanesulfonylphenyl)-2H-pyrazolo[4,3-c]pyridine (75 mg, 0.20 mmol), 4-amino-2,6-dimethylpyrimidine (27 mg, 0.22 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (130 mg, 0.40 mmol) in dioxane (2 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated at 150° C. for 30 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-1% methanol in ethyl acetate) to afford the title compound as a yellow solid (55 mg, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.60 (br s, 1H), 9.21 (s, 1H), 8.32 (s, 2H), 8.30 (s, 1H), 7.99 (d, J=6.4 Hz, 1H), 7.21 (d, J=6.4 Hz, 1H), 3.48 (s, 3H), 2.49 (s, 3H), 2.40 (s, 3H). LCMS (Method B): RT=2.80 min, m/z: 463 [M+H+].
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1[NH:11][N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH3:16])[N:15]=1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[NH:9]([C:10]1[NH:11][N:12]=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]([CH3:16])[N:15]=1)[NH2:8]
Reactant: CC1N=C(NNC(=O)OC(C)(C)C)NN=C1c1ccccc1
Agent: Cl
Product: CC1N=C(NN)NN=C1c1ccccc1
Reaction time: 3.5 h

Procedure:
3-(2-t-Butoxycarbonylhydrazino)-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (5.27 g) was dissolved in a saturated methanolic solution of hydrogen chloride (40 ml), and the solution was allowed to stand at room temperature for 3.5 hours. The reaction mixture was evaporated under reduced pressure and the residual solid was recrystallized from ethanol to give colorless crystals of 3-hydrazino-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine hydrochloride (3.99 g), m.p. 214°~215° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N:36]([CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][O:41]1)=[C:37]=[O:38]>>[O:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH2:39][NH:36][C:37]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:22]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:38]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C=NCC1CCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)NCC6CCCO6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 2-(isocyanatomethyl)tetrahydrofuran (Matrix Scientific, Cat. No. 030196). LCMS (M+H)+: m/z=612.3.
Reaction SMILES: [O:1]1[CH2:11][CH:2]1[CH2:3][C:4]12O[CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9]2.[CH2:12]([CH2:14][NH2:15])[OH:13]>O>[OH:13][CH2:12][CH2:14][NH:15][CH2:11][CH:2]([OH:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1=CC2OC2(CC2CO2)C=C1
Reactant: NCCO
Solvent: O
Product: OCCNCC(O)Cc1ccccc1

Procedure:
The above compound could be made in the same manner as Example 1 using the appropriate epoxide. 1 equivalent of (2,3-Epoxypropyl)benzene oxide and 4 eq. ethanol amine could be stirred at room temperature overnight. The solution could be poured into water and the water is extracted with dichloromethane. The combined dichloromethane layers could be washed with brine and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][NH:22]2)=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][NH:22]3)=[CH:18][CH:17]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc2cn[nH]c2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 6-aminoindazole (3.15 g) in methanol (70 ml) was added N,N-diisopropylethylamine (4.2 ml), and then the solution was reacted at 30-35° C. for 4 hr. The reaction mixture was cooled, and then stirred at 20° C. for 1 hr. The reaction mixture was filtered, washed with methanol (20 ml) and dried at 40-50° C. in vacuo to obtain the desired compound (5.8 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[C:9]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].BrC1C=CC([N:41]2C=C(C(O)=O)[N:43]=[C:42]2[C:49]2C=CC=CC=2Cl)=C(Cl)C=1.C(Cl)(=O)C(Cl)=O.C(=NO)(N)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[CH3:33][S:30]([C:26]1[CH:25]=[C:24]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([C:13]4[O:14][N:43]=[C:42]([CH3:49])[N:41]=4)[N:10]=[C:9]3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[CH:2][CH:3]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:31])=[O:32]
Reactant: O=C(O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)O)nc3Cc3ccccc3Cl)c(Cl)c2)c1
Agent: CC(N)=NO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1noc(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3)c(Cc3ccccc3Cl)n2)n1
Temperature: 0 °C
Yield: 31 %

Procedure:
To a 100 mL round bottom flask was added 1-(3-Chloro-3′-methanesulfonylbiphenyl-4-yl)-2-(2-chlorobenzyl)-1H-imidazole-4-carboxylic acid, obtained in a manner similar to that described for 1-(4-Bromo-2-chloro-phenyl)-2-(2-chlorophenyl)-1H-imidazole-4-carboxylic acid in Example BB1 (350 mg, 707 μmol) and anhydrous CHCl3 (15 mL). The reaction solution was cooled to 0° C. prior to addition of oxalyl chloride (310 μL, 3.54 mmol) and 1 drop of anhydrous DMF. The reaction solution was allowed to stir warming to room temperature over 1.5 h. The solution was concentrated in vacuo and the residue was dissolved in anhydrous 1,4-dioxane (20 mL). To the reaction flask was added acetamide oxime (104 mg, 1.41 mmol) and K2CO3 (293 mg, 2.12 mmol). The mixture was stirred at room temperature for 1 hr prior to addition of xylene (43 mL) and raising the reaction temperature to reflux for 16 hrs. The reaction solution was diluted with EtOAc (100 mL) and washed with sat aq. NH4Cl (150 mL×2). The organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 25 g SiO2 column using a 100% hexane to 100% EtOAc gradient to yield 115 mg (31% yield) of title compound. MS (ESI) 533.3, 535.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.06 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.26 (dd, J=7.8 Hz, J2=1 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.09 (m, 1H), 7.02 (dd, J=7.8 Hz, J2=1 Hz, 1H), 6.95 (t, J=8 Hz, 1H), 3.32 (s, 3H), 2.39 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O>C1COCC1.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc(Cn2cnc3cncnc32)cc1
Temperature: 62.5 °C

Procedure:
To a stirred suspension of 9-benzyladenine (6) (22.0 g, 97.6 mmol) in anhydrous THF (500 mL) was added t-butyl nitrite (9.34 g, 478.5 mmol) and the reaction mixture heated under an atmosphere of nitrogen at 60-65° C. for 4 h. THF and the excess reagent were distilled off and the residue obtained redissolved in chloroform (100 mL) and washed with brine solution (2×50 mL). The chloroform layer was dried over anhydrous sodium sulfate and distilled off to give a reddish oil, which was purified by flash chromatography on silica gel using EtOAc/hexane (8:2) for elution. Yield 10.68 g (42.3%). Mp 99-100° C. 1H NMR (CDCl3): δ 5.49 (s, 2H, CH2), 7.34-7.40 (m, 5H, Ar—H), 8.10 (s, 1H, purine C6—H), 9.06 (s, 1H, purine C8H), 9.20 (s, 1H, purine C2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of di-tert-butyl [4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]imidodicarbonate (1.01 g, 1.58 mmol) in THF (7.9 mL) at room temperature 1.0 M tetra-n-butylammonium fluoride in THF (1.66 mL, 1.66 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using CombiFlash® apparatus (0 to 80% EtOAc in hexanes) to give the sub-title compound (771 mg, 93%). LCMS calc. for C26H43N4O7 (M+H)+: m/z=523.3. Found: 523.2.