Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12]>>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:1]/[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(C#N)n1
Product: CN(C)/C=C/c1cccc(C#N)n1

Procedure:
20 g (169 mmol) of 6-methylpyridine-2-carbonitrile were reacted in a mixture of in each case 100 ml of DMF and DMF-dimethyl acetal in an autoclave at 175° C. overnight. After cooling, the mixture was concentrated by evaporation, the residue was dissolved in dichloromethane, the solution was filtered, the filtrate was concentrated and the residue was subjected to distillation under reduced pressure in a kugelrohr.
Reaction SMILES: [Cl:1][CH:2]([Cl:35])[C:3]([N:5]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:13]=2)[CH:7]=1)=[O:4].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:27][CH2:26][CH2:25][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:13]=2)[CH:7]=1)[C:3](=[O:4])[CH:2]([Cl:1])[Cl:35]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1

Procedure:
tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate (100 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (3 mL) and cooled in an ice-bath under nitrogen. Then trifluoroacetic acid (3 mL) was added. After 3 h at 4° C. the mixture was concentrated under reduced pressure. The residue was dissolved and concentrated under reduced pressure again to give N-(2-aminoethyl)-2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamide trifluoroacetate salt as a white solid. 1H NMR (CDCl3): 8.04 (s, 1H), 7.65-7.62 (m, 2H), 7.43-7.30 (m, 4H), 6.73 (s, 1H), 5.95 (s, 1H), 4.21 (m, 2H), 3.35 ppm (m, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[C:14]([F:15])=[CH:13][NH:12][CH:11]=1.B(F)(F)F>C(Cl)Cl>[F:9][C:10]1[C:14]([F:15])=[C:13]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]3[N:12]=[C:11]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]4[NH:12][C:11](=[C:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:11]5[C:10]([F:9])=[C:14]([F:15])[C:13](=[C:1]([C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[C:11]=1[NH:12]2)[N:12]=5)[C:10]([F:9])=[C:14]4[F:15])[C:10]([F:9])=[C:14]3[F:15]
Reactant: Fc1c[nH]cc1F
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: FC1=C(F)c2nc1c(-c1ccccc1)c1[nH]c(c(F)c1F)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3[nH]c(c(F)c3F)c2-c2ccccc2)C(F)=C1F
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Benzaldehyde (0.35 mL, 3.5 mmol), 3,4-difluoropyrrole (0.33 g, 3.2 mmol), and 250 mL of distilled CH2Cl2 were placed under N2 in a 500 mL round-bottom flask equipped with a magnetic stir bar. The reaction was stirred while BF3 etherate (0.5 mL, 3.9 mmol) was added via syringe. To monitor the reaction, aliquots were periodically removed from the reaction vessel, oxidized with DDQ, neutralized with pyridine, and chromatographed by silica gel TLC using CHCl3 as eluent. After 30 minutes, DDQ (1 g) and pyridine (5 mL) were added. The reaction was stirred for 12 hours, filtered through a short silica gel column using CH2Cl2 as eluent, and evaporated. The resulting solid was washed three times with 10 mL of pentane followed by three washes with 10 mL of ethanol. The product was recrystallized from toluene/hexane by layering to yield 127 mg of pure 2,3,7,8,12,13,17,18-octafluoro-5,10,15,20-tetraphenylporphyrin in 21% yield (first crop). A second crystallization using identical conditions yielded an additional 75 mg for a total isolated yield of 33%. The product is characterized by the following data: 1H NMR (360 MHz, CDCl3) δ 8.03 (d, 8H, J1 =6.7 Hz), 7.74 (m, 12H), -4.18 (s, 2H); 19F NMR (500 MHz, CDCl3, -50° C.) δ -141.1 (s, 4F), -146.4 (s, 4F); UV-vis (CH2Cl2) 402 (5.31), 499 (4.21), 532 (3.71), 581 (3.55), 637 (3.60); low resolution FAB MS 758 (calcd 758). Anal. Calcd for C44H22F8N4 : C, 69.66; H, 2.92; N, 7.38. Found: C, 69.43; H, 2.90; N, 6.95.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:7]1=[O:26].C([SiH](CC)CC)C.C(OCC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:11][C:9]1([CH3:12])[CH2:10][NH:6][C:7](=[O:26])[CH:8]1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:24])([F:23])[F:25])[CH:15]=1
Reactant: COc1ccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A solution of 4-[1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy]-2-trifluoromethyl-benzonitrile (25 g; 56 mmol) in trifluoroacetic acid (250 mL)and triethylsilane (20 g; 169 mmol; 3 eq) was brought to gentle reflux overnight. The reaction was cooled to ambient temperature. The reaction mixture was concentrated in vacuo to give an oily residue. The crude product was dissolved in dichloromethane and was washed with saturated aqueous sodium bicarbonate and with brine solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark purple oily residue. The product was purified by flash silica column chromatography. Elution with a gradient (100% hexanes to 3:2 v/v ethyl acetate-hexanes over 1 hour, 12 minutes; pump speed: 1 mL/min) afforded an off-white powder. Trituration with diethyl ether over a steam bath afforded 14.6 g of a white powder; 1H-NMR (400 MHz; CDCl3) δ 7.75 (dd, 1H, J=8.6, 0.4 Hz), 7.46 (d, 1H, J=2.5 Hz), 7.37 (dd, 1H, J=8.6, 2.5 Hz), 6.46 (s, 1H), 4.53 (s, 1H), 3.21 (s, 1H), 3.20 (s, 1H), 1.27 (s, 3H), 1.25 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ −62.66 (s, 3F); MS (APCl+) 299.1 (M+1, 100); (APCl−) 186.0 (100)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](#[N:21])[CH3:20]>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:2]([NH:1][C:19](=[NH:21])[CH3:20])[CH:7]=1
Reactant: Cc1ccc(N2CCOCC2)c(N)c1
Reactant: CC#N
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=N)Nc1cc(C)ccc1N1CCOCC1

Procedure:
A mixture of 4-(2-amino-4-methylphenyl)morpholine (5.76 g), acetonitrile (3.5 g) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for 5 hours to yield N-(5-methyl-2-morpholinophenyl)acetamidine (m.p. 121° C.) which was recrystallised from hexane.
Reaction SMILES: [N:1]1[C:2](=[O:9])[NH:3]C(=O)C(=O)C=1.C(O[C:13]([C:15]1([C:39]([O:41]CC)=O)[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[N:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[N:37][N:38]=3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:14])C.NC(N)=O>[O-]CC.[Na+].C(O)C>[O:35]1[CH:36]=[N:37][N:38]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[N:23]=[CH:22][C:21]([N:16]3[C:15]4([C:39](=[O:41])[NH:3][C:2](=[O:9])[NH:1][C:13]4=[O:14])[CH2:19][CH2:18][C:17]3=[O:20])=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(-c3nnco3)cc2)nc1
Reactant: O=C1N=CC(=O)C(=O)N1
Agent: CC[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C2(CCC(=O)N2c2ccc(Oc3ccc(-c4nnco4)cc3)nc2)C(=O)N1

Procedure:
Following the procedure for pyrimidinetrione formation outlined in Example 1, reaction of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (200 mg, 0.44 mmol) with urea (0.080 g, 1.3 mmol) in 1.3 mL of 1M sodium ethoxide in ethanol afforded 25 mg of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4,5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD3OD, 500 MHz): 9.02 (s, 1H), 8.14 (d, 2H, J=8.0 Hz), 8.06 (d, 1H, J=2.0 Hz), 7.78 (dd, 1H, J=2.5, 9.0 Hz), 7.35 (d, 2H, J=9.0 Hz), 7.12 (d, 1H, J=9.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H) ppm. MS (APCl, m/z): 435 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:9][CH:8]=1)(=O)=O.C[Sn](C)(C)[C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.C(N(CC)CC)C.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([C:14]2[C:15]3[C:10](=[CH:9][CH:8]=[C:7]([C:28]4[CH:29]=[N:30][CH:31]=[N:32][CH:33]=4)[CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2cccc3ccc(OS(=O)(=O)C(F)(F)F)cc23)CC1
Reactant: C[Sn](C)(C)c1cncnc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(-c4cncnc4)cc23)CC1
Yield: 29.9 %

Procedure:
A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.250 g, 0.67 mmol), bis(triphenylphosphine)palladium[11]chloride (0.025 g, 0.036 mmol), 5-trimethylstannylpyrimidine (0.178 g, 0.74 mmol, from Preparation 6), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N, N-dimethylformamide (12.5 mL) was heated between 100° C. to 115° C. under nitrogen for 45 minutes. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]to afford the title compound (0.060 g, 0.20 mmol, 29%) as a pale yellow foam: Rf =0.15 in 20% methanol in ethyl acetate; 13C NMR (CDCl3) δ 157.3, 155.0, 149.8, 134.6, 134.5, 130.8, 129.9, 129.0, 127.1, 124.0, 123.4, 122.1, 116.0, 55.4, 52.7, 45.9; LRMS (m/z, relative intensity) 304 (M+, 7), 240 (100), 225 (15), 196 (16), 169 (44), 155 (33), 141 (16); HRMS m/e calculated for C19H20N4 304.1690. Observed m/e 304.1689.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>O1CCCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:9]=1[CH2:10][NH:11][C:17](=[O:18])[NH:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1c(N)cccc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C1NCc2c(cccc2Oc2ccccc2)N1
Temperature: 25 °C

Procedure:
The product of example 2b above, 2-phenoxy-6-aminobenzyl amine, (0.22 g 1.03 mol) was dissolved in dry tetrahydrofuran (8 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.2 g, 1.24 mmol) dissolved in dry tetrahydrofuran (2 mL) was added and the mixture stirred at room temperature. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted wit 0–10% methanol in methylene chloride to give the title compound as a white amorphous solid. mp 278–280° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=1[Cl:17])[CH3:5].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:15][C:14]1[CH:13]=[C:12]([Cl:16])[CH:11]=[C:10]([Cl:17])[C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[CH:4]([NH:3][O:2][CH3:1])[CH3:5]
Reactant: CON=C(C)C1CC1c1c(Cl)cc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CONC(C)[C@@H]1C[C@H]1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-[2-(2,4,6-trichloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime (0.19 mmol), prepared as described in example P23, in ethanol (1 ml) and acetic acid (1 ml) was treated at ambient temperature with sodium cyanoborohydride (200 mg, 3.18 mmol) added in one portion. The resulting solution was stirred at ambient temperature for 20 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with 1 M NaOH (5 ml). The aqueous phase was extracted with ether (3×10 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (5 g) (eluent: c-hexane/ethyl acetate 5:1). 25 mg (45.0% of theory) of trans-N-{1-[2-(2,4,6-trichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine as a mixture of diastereomeres was obtained in form of a clear liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:38]([NH:42]CC1C=CC(OC)=CC=1)[CH:39]([CH3:41])[CH3:40])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[NH2:42][CH:38]([P:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([O:27][C@@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:29])[CH:39]([CH3:41])[CH3:40]
Reactant: COc1ccc(CNC(C(C)C)P(=O)(OCc2ccccc2)O[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: CC(C)C(N)P(=O)(OCc1ccccc1)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
The crude benzyl (S)-6-benzyloxycarbonylamino-2-((1-((4-methoxy)benzylamino)-2-methylpropyl)(benzyloxyphosphinoyl)oxy)hexanoate (557.4 mg) obtained in the above step (d) was dissolved in a mixed solvent of acetonitrile and water (4:1) (5.6 ml). Cerium(IV) diammonium nitrate was dissolved in a mixed solvent of acetonitrile and water (4:1) (5.6 ml), and the resulting solution was added to the reaction system. The mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C. and added with saturated aqueous sodium thiosulfate, and further stirred at room temperature for 30 minutes. The organic substances were extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure, and then the residue was roughly purified by silica gel column chromatography (25 g, hexane:ethyl acetate:acetic acid=250:50:1.5 to chloroform:methanol=30:1) to obtain crude benzyl (S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanoate (271 mg, 62%). This compound was examined in the molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of 1 (1.65 g, 5.50 mmol) in CH2Cl2 (4 mL) was added 4 Å molecular sieves (4.5 g) and PCC (2.36 g, 11 mmol). Then the mixture was stirred for 2 hours, filtered through silica gel column until the filtrate was nearly colorless. The filtrate was evaporated to dryness and the crude product (1.4 g, 82%) was obtained and was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9 H), 2.97-3.16 (m, 2 H), 4.63 (s, 1H), 5.17 (s, 2 H), 5.40 (d, 1 H), 7.33 (m, 5 H), 9.71 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Br:31])[CH:19]=[CH:18]4)[N:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[Br:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:13]3[N:12]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)[C:9]4=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]4[N:14]=3)[CH:16]=2)[N:21]=1
Reactant: CCOC(=O)c1cnc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)ccc3c1)n2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)ccc3c1)n2C1CCCCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Compound 477d (0.139 g, 0.25 mmol) was dissolved in MeOH (3 mL) and 2 N aqueous NaOH (1.5 mL) was added. The mixture was stirred at 55° C. for 2 h and then neutralized with 5 N HCl to pH 3 at 0° C. The precipitates formed was collected by filtration and purified by RP HPLC (15% of buffer B to 95% of buffer B) to give the title compound. Yield 96%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:52]3[CH2:53][CH2:54][CH:49]([N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH2:50][CH2:51]3)=[O:22])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: C1CCN(C2CCNCC2)CC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(N4CCCCC4)CC3)(CC1)CC2
Yield: 84.9 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(piperidin-1-yl)piperidine (22.0 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-(piperidin-1-yl)piperidin-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (44.9 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH2:47])[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1>C1COCC1>[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH:47][C:10](=[O:12])[CH3:11])[C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:34][CH:35]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 27.1 %

Procedure:
Step (b) DIEA (0.10 mL, 0.57 mmol) and acetic anhydride (0.025 mL, 0.27 mmol) was added to (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-amino-N-(4-(4-fluorophenoxy)phenyl)pentanamide (115 mg, 0.269 mmol) in THF (5 mL). The reaction mixture was stirred for 2 hours and then concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 254, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-acetamido-N-(4-(4-fluorophenoxy)phenyl)pentanamide (34 mg, 0.073 mmol, 27%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.21 (s, 1H), 8.75-8.73 (m, 1H), 8.47 (s, 1H), 7.85-7.82 (m, 1H), 7.63-7.58 (m, 2H), 7.24-7.18 (m, 2H), 7.04-6.92 (m, 4H), 4.99 (s, 2H), 4.46-4.38 (m, 1H), 3.12-3.01 (m, 2H), 1.80 (s, 3H), 1.79-1.37 (m, 4H). MS (EI) for C23H25FN6O4. found 469.1 (MH+).
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[Br:1][CH:14]([CH3:15])[CH2:13][CH2:12][C:11](=[O:16])[C:9]([N:6]1[C:5](=[O:18])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([CH3:2])[O:8][CH2:7]1)([CH3:10])[CH3:17]
Reactant: C=CCCC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: Br
Solvent: CC(=O)O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)Br)CO1
Reaction time: 5 h

Procedure:
Hydrogen bromide solution in acetic acid (50 g of 30% w/w) was added to 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-hept-6-en-3-one (4.14 g) and stirred for 5 hours. Evaporation and dry column chromatography on silica gel eluting with hexane/ethyl acetate (4:1) gave 6-bromo-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-heptan-3-one (1.04 g) as a brown gum, NMR 1.4(s,6H), 1.7(d,3H), l.9(m,1H), 1.9(s,3H), 2.2(m,1H), 2.7(m,2H), 4.1(m,1H), 5.3(s,2H), 7.3(m,5H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([NH2:16])[CH:15]=[C:10]3[CH:9]=[N:8]2)[CH2:3][CH2:2]1.O1CCC(C=O)C1>>[O:1]1[CH2:2][CH2:3][CH:5]([CH2:4][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([NH2:16])[CH:15]=[C:10]3[CH:9]=[N:8]2)[CH2:6]1
Reactant: Nc1cnc2c(cnn2C2CCOCC2)c1
Agent: O=CC1CCOC1
Product: Nc1cnc2c(cnn2CC2CCOC2)c1

Procedure:
1-(Tetrahydro-furan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-5-ylamine is synthesized using a similar procedure used to prepare (1-(Tetrahydro-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-ylamine (Intermediate P), replacing tetrahydropyran-4-one with tetrahydro-furan-3-carbaldehyde in Step 1.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][N:3]2[C:7](=[O:12])[NH:8][C:9](=[O:11])[CH:10]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]1[C:9](=[O:11])[CH:10]=[C:2]2[S:1][CH2:6][CH2:5][CH2:4][N:3]2[C:7]1=[O:12]
Reactant: O=c1cc2n(c(=O)[nH]1)CCCS2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc2n(c(=O)n1CCCCCl)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.76 g (15 mmol) of 3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.32 g (24 mmol) of potassium carbonate in 50 ml of N,N-dimethyl-formamide, 3.46 ml (30 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1→1/4) to yield 1.92 g (46.6%, white powder) of the desired product.