Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH3:22])[CH:6]([N:8]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH3:22])[CH:6]([N:8]([C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1N)C1CC1
Yield: 72.5 %

Procedure:
A mixture of 1.02 g (0.003 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (IV-46) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 0.68 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (V-46). This material was used directly in the next step without further purification.
Reaction SMILES: N(OC(C)(C)C)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.C[Si]([N:22]=[N+:23]=[N-])(C)C>CC#N>[N:8]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[N+:22]=[N-:23]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
Neat tert-butyl nitrite (670 μL, 5633 μmol) was added to a suspension of 5-aminoindazole (500 mg, 3755 μmol) (commercially available from VWR Chemical Catalog (Order Number AAAL06705-14)) in MeCN (7 mL) at 0° C. followed by dropwise addition of trimethylsilyl azide (598 μL 4506 μmol). The mixture was stirred at 0° C. for 5 minutes room temperature for 18 hours, and at 50° C. for 24 hours. The mixture was concentrated under reduced pressure, and the resulting brown residue was absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 6% MeOH/DCM) to provide 5-azido-1H-indazole (456 mg, 76%) as a golden solid. LCMS (API-ES) m/z: 160.1 (M+H+).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)SC)#[N:2].O.[NH2:22][NH2:23]>C(O)C>[NH2:2][C:1]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[N:22][N:23]=1
Reactant: CSC(=NC#N)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nnc(N2CCN(Cc3ccc(F)cc3)CC2)[nH]1

Procedure:
The entire portion (0.1 mole) of N-cyano-4-(p-fluorobenzyl)-1-piperazinecarboximidothioic acid, methyl ester, prepared as an oil (Example 27) was dissolved in 150 ml. of ethanol and 5.5 ml. (0.11 mole) of hydrazine hydrate were added. The mixture was refluxed for 6 hours and then evaporated to a solid residue which as crystallized from 200 ml. of ethanol, giving 21 g. of the desired product as colorless crystals, m.p. 213°-216° C. (dec.).
Reaction SMILES: [Li].BrC1C=CC=CC=1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[CH3:18][N:19]([CH3:22])[C:20]#[N:21]>O.C(OCC)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=[C:20]([N:19]([CH3:22])[CH3:18])[N:21]=1
Reactant: N#Cc1ccccc1N
Reactant: CN(C)C#N
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CN(C)c1nc(N)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere 0.7 g. (0.10 g. at.) of lithium and 7.85 g. (0.05 mol) of bromobenzene are dissolved in 60 ml. of anhydrous diethyl ether. Over the course of about 20 minutes this solution is added to a solution of 5.9 g. of o-aminobenzonitrile in 60 ml. of anhydrous diethyl ether. After 10 minutes, 3.5 g. of dimethylcyanamide, dissolved in 20 ml. of anhydrous diethyl ether, are added and the reaction mixture is refluxed under the nitrogen atmosphere for 6 hours. The next day the mixture is decomposed by addition of water and the precipitate is filtered off. The product is crystallized from a mixture of ethanol and petroleum ether (boiling range 28°-40°C.). 6 g. of 4-amino-2-dimethylaminoquinazoline, m.p. 141°-142°C., are obtained.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]([O:25][CH3:26])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)C1C=CC=CC=1.[H][H].ClCCl>CO.[C].[Pd]>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]2[NH:14][C:9](=[O:8])[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]=2[O:25][CH3:26])=[CH:17]1
Reactant: COc1c(Cc2c[nH]c3ccccc23)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1c(Cc2c[nH]c3ccccc23)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Reaction time: 0.33 h
Yield: 92 %

Procedure:
In 140 ml of methanol was dissolved 2.69 g of 3-benzyloxy-5-(indol-3-yl)methyl-2-isobutyl-6-methoxypyrazine 1-oxide, thereto was added 10% palladium-carbon, and the mixture was stirred for 1 hour at room temperature in a hydrogen gas atmosphere. 150 Milliliters of dichloromethane was added, and the mixture was stirred for 20 minutes, then the catalyst was removed by filtration, and the filtrate was subjected to recrystallization from methanol-chloroform to obtain 1.94 g of the title compound as pale yellow prism-like crystals having a melting point of 222°-224° C.
Reaction SMILES: FC1C=CC2O[C@H](C)[C@H]([N:13]([CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])C(=O)N(CCO)C=2C=1>C(O)(C)C.CCCCCCC>[OH:20][C:15]([CH3:19])([C:16]([NH2:18])=[O:17])[C:14]([NH:13][CH2:22][C:23]([F:28])([F:29])[C:24]([F:27])([F:26])[F:25])=[O:21]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CC(O)(C(N)=O)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
0.31 g (1.0 mmol) N-[(6R,7S)-2-Fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide epimers were separated by chromatography on Chiralpak AD with isopropanol/heptane 15:85 to yield 0.11 g N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity A, MS m/e (%): 502.3 (M+H+, 100) and 0.08 g N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity B, MS m/e (%): 502.1 (M+H+, 100).
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:12]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH3:30])=[N:11]2)=O)(C)(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])=[N:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:6]#[N:5])[CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1
Reactant: C[C@H]1CCCN1c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@H]1CCCN1c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)—N-tert-butyl-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxamide (160 mg, crude) in dichloromethane (30 mL) was added TFAA (4 mL). The resulting solution was stirred overnight at room temperature and then quenched by the addition water (100 mL), adjusted to pH 7 with sodium bicarbonate, and extracted with dichloromethane (3×30 mL). The organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carbonitrile as a yellow solid (100 mg, 53%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 48.9 %

Procedure:
Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (30:1) gave 83 mg (49%) of product as a colorless hard foam.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH2:19][OH:20])[NH:6][C:7]=1[C:8]1[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O)#[N:2].CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:39][C:40]1([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:43][NH:42][CH2:41]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([C:40]2([F:39])[CH2:43][N:42]([C:13]([C:12]3[C:11]([CH3:17])=[CH:10][C:9]([CH3:18])=[C:8]([C:7]4[NH:6][C:5]([CH2:19][OH:20])=[N:4][C:3]=4[C:1]#[N:2])[CH:16]=3)=[O:15])[CH2:41]2)=[CH:45][CH:46]=1)#[N:49]
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C#N)cc1C(=O)O
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C#N)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 219.6) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 430 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:18])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16]>C(OCC)(=O)C.[Pd]>[CH3:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:18])[CH3:1]
Reactant: CC(=O)CCC=CCCCCC=CCCC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCCCCCCCCCCCC(C)=O

Procedure:
38 g of hexadeca-5,11-diene-2,15-dione (0.152 mole) were dissolved in 200 ml of ethyl acetate and hydrogenated at 50° C. under standard conditions using 1.9 g of 10% strength Pd/C. Recrystallization from petroleum ether gave 25.8 g of a 97% strength hexadecane-2,15-dione of melting point 80° C. The yield was thus 66% of theory.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][CH2:51]3)=[CH:46][N:45]=2)[C:29]1=[O:60].C1COCC1>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].O>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:32]3[CH:31]=[C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH:56]6[CH2:57][O:58][CH2:59]6)[CH2:52][CH2:51]5)=[CH:46][N:45]=4)[C:29](=[O:60])[N:28]([CH3:27])[CH:33]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(F)cc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 59.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (100 mg, 0.24 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O(149 mg, 0.56 mmol), THF (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 102c as a yellow solid (98 mg, 60%). LCMS: [M+H]+ 682
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: C[O-]
Reactant: CN1CCC(CCCOc2cc(Cl)c(C#N)cn2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (Example 115) in methanol (0.2 M) was treated with sodium methoxide (4 equiv) at reflux temperature for 4 h. The mixture was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with chloroform. The organic extract was dried (Na2SO4), filtered, and concentrated to yield 4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (100%). This intermediate was converted to the title compound according to Example 115. MS (electrospray): mass calculated for C23H30ClN4O2, 394.24; m/z found, 395.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]=1[NH:22][C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:39]=[CH:38][N:37]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:36]=2)=[O:34])=[CH:28][CH:27]=1)=O.[OH-].[Na+].Cl>CO>[CH2:8]([N:7]1[C:2]2[N:1]=[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]4[N:39]=[CH:38][N:37]([C:40]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:36]=4)=[O:34])=[CH:30][CH:31]=3)[NH:22][C:3]=2[C:4](=[O:21])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]1=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (70 mg, 0.09 mmol) in methanol (3.0 mL) heated to 50° C. was treated with a 10% aqueous sodium hydroxide solution (1.08 mL). The reaction was heated at 50° C. for 4 h. At this time, the reaction was treated with a 3N aqueous hydrochloric acid solution (0.9 mL). This solution was stirred at 25° C. for 30 min. The resulting solids were collected by filtration, washed with water, and dried in vacuo to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (41.3 mg, 60.5%) as a pale yellow solid: EI-HRMS m/e calcd for C45H39N8O3F (M+Na)+781.3027, found 781.3039.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[O-:26])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]3[N:43]=[CH:42][NH:41][C:40]=3[CH:44]=2)O1>>[NH:41]1[C:40]2[CH:44]=[CH:36][C:37]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[C:5]4[NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:27])[O:26][C:4]([CH3:9])([CH3:5])[CH3:3])[CH2:22][CH2:23]3)=[CH:38][C:39]=2[N:43]=[CH:42]1
Reactant: CC1(C)OB(c2ccc3nc[nH]c3c2)OC1(C)C
Reactant: O=C([O-])N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc5[nH]cnc5c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl [trans-4-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (49 mg, 0.200 mmol) to afford the desired product (45.3 mg, 86%) as an off-white solid: ESI MS m/z 526 [C31H35N5O3+H]+.
Reaction SMILES: [Na].[CH:2]1[C:7]([CH:8]([OH:11])[CH2:9][NH2:10])=[CH:6][CH:5]=[C:4]([OH:12])[CH:3]=1.[CH2:13]([C:17]1[CH:32]=[CH:31][C:20]([O:21][CH2:22][C:23]2[O:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=2)=[CH:19][CH:18]=1)[C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>CO>[OH:11][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([OH:12])=[CH:3][CH:2]=1)[CH2:9][NH:10][CH:14]([CH3:16])[CH2:13][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]2[O:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=2)=[CH:31][CH:32]=1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the sodium salt of octopamine (0.65 g), and 2-(4-acetonylphenoxymethyl)-5-hydroxy-4H-pyran-4-one (1.0 g) in methanol was treated with sodium cyanoborohydride (0.3 g) and stirred at ambient temperature for 18 hours. The solvent was evaporated in vacuo. The residue was suspended in acetone and filtered, washed with acetone and then purified by column chromatography on silica using 5% methanol:chloroform as eluent-increasing to 15% methanol:chloroform after elution of fast-running impurities. This gave 2-[4-[2-[(β,4-dihydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one(0.4 g) as a (50:50) mixture of diastereoisomers.
Reaction SMILES: C(=[N:14][C:15]1[N:16]=[C:17]2[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]2=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:14][C:15]1[N:16]=[C:17]2[C:23]([C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:18]2=[N:19][CH:20]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N=C(c3ccccc3)c3ccccc3)nc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 1-[2-(benzhydrylidene-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.670 g, 1.31 mmol), sodium acetate (0.258 g, 3.14 mmol) and hydroxylamine hydrochloride (0.164 g, 2.36 mmol) in 13 mL of methanol was stirred for 1 h, then concentrated to a residue. Column chromatography (10→50% EtOAc/hexanes) afforded 0.359 g (79%) of 1-[2-amino-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH:14]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[S:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: SC1CCCC1
Reactant: COC(=O)c1ccc(OC)nc1Cl
Product: COC(=O)c1ccc(OC)nc1SC1CCCC1
Yield: 77 %

Procedure:
2-Chloro-6-methoxy-nicotinic acid methyl ester (54 mg, 0.26 mmol) and cyclopen-tanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (55 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>>[Cl:18][C:6]1[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)nc(C)[nH]c1=O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(C)nc(C)nc1Cl
Yield: 98 %

Procedure:
A mixture of ethyl (2,6-dimethyl-3H-pyrimidin-4-on-5yl)acetate (1.13 g, 5.4 mmol), phosphorous oxychloride (10 mL, and N,N-dimethylaniline (1.3 mL, 10.3 mmol) was heated under reflux for 3.5 h. The reaction mixture was concentrated, poured onto ice, and the resulting mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4), and concentrated to give 1.2 g (98%) of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4](Cl)[N:3]=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1nccc(NCC2(CO)CCC2)n1

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (1.46 g, 6.0 mmol) were added ethanol (40 ml), cyclohexene (15 ml) and palladium hydroxide (0.2 g) in a nitrogen stream, and the mixture was refluxed for 2 hours. The reaction mixture was filtered and the solvent in the filtrate was distilled away under reduced pressure to give white amorphous crystals (1.34 g, quantitative).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH:33]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:32][C:31]([CH2:43]Br)=[CH:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH:33]([CH2:34][OH:35])[CH2:32][C:31]([CH2:43][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:30]1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CC(CO)C(CO)C2)c(=O)[nH]c1=O
Yield: 17.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (42 mg).