Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[OH:13][C@H:14]1[C@@H:19]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:17][CH2:18][C@H:19]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:14]([OH:13])[CH2:15]2)=[CH:7][CH:8]=1
Reactant: O=C(N[C@H]1CCNC[C@H]1O)c1ccccc1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O)c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 4.1 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 4.4 parts of cis-N-(3-hydroxy-4-piperidinyl)-benzamide, 3.8 parts of sodium carbonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours. The reaction mixture was cooled to room temperature and washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 4.2 parts (57%) of cis-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]benzamide; mp. 130.5° C. (compound 42).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[CH2:20]([C@@H:22]1[O:24][CH2:23]1)[Cl:21]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][C@@H:22]([OH:24])[CH2:20][Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CCl)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (commercial; 1.40 g, 7.6 mmol) in dry MeOH (25 mL) was treated with MgSO4 (1.9 g). (R)-Epichlorohydrin (1.47 mL, 18.9 mmol) was added dropwise and the mixture was heated at 35° C. for 2 h and was then stirred at rt overnight. The mixture was filtered over Celite and concentrated under reduced pressure. The residue was taken up in DCM and washed with water. The org. phase was dried over MgSO4 and concentrated under reduced pressure to afford the crude 4-((R)-3-chloro-2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester. To a solution of the above intermediate chlorohydrin (2.10 g, 7.53 mmol) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (2.15 g, 1 eq, prepared according to WO2007107965) in DMF (30 mL) was added LiOtBu (10.3 mL, 2.2M in THF) at rt. The mixture was stirred at rt over night and subsequently at 50° C. for 5 h. The mixture was partitioned between EA and 0.5M HCl. The aq. phase was basified (NH4OH) and extracted with EA. The org. layer was dried over MgSO4 and concentrated under reduced pressure to afford the title compound as a colorless solid (1.15 g, 36%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:26])[NH:12][C:13](=[O:25])[N:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[CH3:28]>>[Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:26])[N:12]([CH3:28])[C:13](=[O:25])[N:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:15]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Product: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 16 (Step 1), starting from 5-[[tert-butyl(dimethyl)silyl]oxymethyl]-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide (0.14 g, 0.37 mmol); iodomethane was used herein and the reaction was stirred under nitrogen at room temperature for 45 minutes. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 90:10) to afford the title compound (0.055 g, 37%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.12 (s, 6H), 0.90 (t, J=6.6 Hz, 3H), 0.95 (s, 9H), 1.29-1.41 (m, 6H), 1.57-1.65 (m, 2H), 3.36 (s, 3H), 3.40 (td, J=7.1, 5.7 Hz, 2H), 4.53 (d, J=1.7 Hz, 2H), 8.47 (t, J=1.6 Hz, 1H), 9.32 (t, J=4.5 Hz, 1H). MS (ESI) m/z: 398 [M-H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([N+:11]([O-])=O)=[C:4]([N+:14]([O-])=O)[C:3]=1[O:17][CH3:18]>CCO.[Pd]>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([NH2:11])=[C:4]([NH2:14])[C:3]=1[O:17][CH3:18]
Reactant: COc1c(C)c(C)c(OC)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(N)c1N
Reaction time: 3 h
Yield: 81.9 %

Procedure:
2,3-Dimethyl-5,6-dinitro-1,4-dimethoxybenzene (4.0 g; 15 mmol) in EtOH (120 mL) was heated to solution, and 10% palladium on charcoal (1.0 g) was added.. The reaction mixture was hydrogenated at 45 psig for 3 hours. After work-up, 2.41 g (83% yield) of 2,3-dimethyl-5,6-diamino-1,4-dimethoxybenzene was obtained as a yellow solid, m.p. 107-110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])OC)=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11].[NH2:39][C:40]#[N:41]>CO>[C:40]([NH:41][C:28](=[NH:31])[C:25]1[CH:26]=[CH:27][C:22]([C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C@H:10]([CH3:11])[C@:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])([OH:38])[CH2:32][N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH:13]=[N:14][C:15]=3[CH:21]=2)=[CH:23][CH:24]=1)#[N:39]
Reactant: COC(=N)c1ccc(-c2cc3ncn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c(=O)c3s2)cc1
Reactant: N#CN
Solvent: CO
Product: C[C@@H](n1cnc2cc(-c3ccc(C(=N)NC#N)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (1R,2R)-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-6-[4-[imino(methoxy)methyl]phenyl]thieno[3,2-d]pyrimidin-4(3H)-one (0.35 mg, 0.652 mmol) (obtained in example 63) and NH2CN (140 mg, 3.26 mmol) in MeOH (15 mL) was refluxed overnight. The solvent was removed by concentration and the residue was partitioned between CHCl3 and 10% NaHCO3 solution. The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound as a white solid: mp 275°-278° C.; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.61 (s, 1H, N=CH--N), 8.18 (s, 1H, triazole), 8.02 (d, J=8.5, 2H, arom), 7.95 (d, J=8.5, 2H, arom), 7.81 (s, 1H, thiophene), 7.66 (s, 1H, triazole), 7.43 (dt, Jt =6.5, Jd =9, 1H, arom), 7.08 (ddd, Jd =2.5, Jd =8.5, Jd =14, 1H, arom), 6.89 (dt, Jd =2.5, Jt =8.5, 1H, arom), 6.09 (q, J=7.3, 1H, MeCH), 5.09 (d, J=14.2, 1H, CH(H)), 4.19 (d, J=14.2, 1H, CH(H)), 1.33 (d, J=7.3, 3H, CHMe); [α]D =+43.0° (c 0.25, MeOH). Analysis calculated for C26H20F2N8O2S.H2O: C 55.31; H 3.93; N 19.85; S 5.68. Found: C 55.06; H 3.74; N 18.57; S 5.28.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@H:15]2[C:21](=[O:22])[N:20]3[C@@H:16]2[CH2:17][C:18](=O)[C@@H:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[SH:63][C@@H:64]1[CH2:68][N:67]([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=2)=[O:70])[C@H:66]([CH2:82][S:83][C:84]2[CH:89]=[CH:88][N:87]=[CH:86][CH:85]=2)[CH2:65]1>ClCCl>[N+:79]([C:76]1[CH:75]=[CH:74][C:73]([CH2:72][O:71][C:69]([N:67]2[CH2:68][C@@H:64]([S:63][C:18]3[CH2:17][C@H:16]4[N:20]([C:21](=[O:22])[C@@H:15]4[C@H:13]([O:12][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:38][CH:37]=4)=[O:11])[CH3:14])[C:19]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:65][C@H:66]2[CH2:82][S:83][C:84]2[CH:89]=[CH:88][N:87]=[CH:86][CH:85]=2)=[O:70])=[CH:78][CH:77]=1)([O-:81])=[O:80]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSc1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4ccncc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.2 g) in dry dichloromethane (40 ml) were added N,N-diisopropyl-N-ethylamine (0.44 ml) and trifluoromethanesulfonic anhydride (0.40 ml) at -40° C., and the solution was stirred at the same temperature for 15 minutes. To this solution were added N,N-diisopropyl-N-ethylamine (0.63 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-(pyridin-4-ylthiomethyl)pyrrolidine (1.38 g) in dry dichloromethane (5 ml) successively at the same temperature under an atmosphere of nitrogen, and stirred at ambient temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (4:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(pyridin-4-ylthiomethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]1[CH2:8][CH2:7]1)=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:8][CH2:7][N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)([OH:26])[CH2:25][CH2:24]1)=[O:5]
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccccc1Br)N1CC1
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1Br

Procedure:
A mixture of 2.26 parts of 1-(2-bromobenzoyl)aziridine, 2.12 parts of 4-(4-chlorophenyl)-4-piperidinol, 10.8 parts of benzene and 0.8 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled and evaporated. The residue is crystallized from ethyl acetate. The product is filtered off and dried, yielding 2.5 parts of 2-bromo-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}benzamide; mp. 120.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:23])[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate as a TFA salt (73 mg, 0.17 mmol) in DCM (4.0 mL) was added TFA (1.0 mL). The solution was stirred at room temperature for 2 h and the solvent was removed in vacuo to give 4-(4-amino-2-fluorobenzyl)pyridin-2-amine, bis-trifluoroacetic acid (70 mg, 93% yield). MS(ESI+): m/z 218.12 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][O:14]C(C)(C)[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO>[CH2:1]([S:8][CH2:9][C:10]([CH2:15][OH:14])([C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(CSCc2ccccc2)(C(C)(C)C)CO1
Solvent: O
Solvent: CO
Product: CC(C)(C)C(CO)(CO)CSCc1ccccc1
Reaction time: 3 h

Procedure:
5-Benzylthiomethyl-5-t-butyl-2,2-dimethyl-1,3-dioxane (7.0 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (0.6 g.) in methanol (100 ml.) containing water (10 ml.) was refluxed, with stirring, for 3 hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Benzylthiomethyl-2-hydroxymethyl-3,3-dimethyl-butan-1-ol was obtained as a colourless oil (5.0 g.) and was used without further purification.
Reaction SMILES: C[C@H]1CC2(CCN(C(OC(C)(C)C)=O)CC2)C(=O)N1.[CH3:20][CH:21]1[CH2:25][C:24]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:23](=[O:31])[N:22]1[C:32]1[CH2:33][O:34][C:35](=[O:37])[CH:36]=1>>[CH3:20][C@H:21]1[CH2:25][C:24]2([CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[C:23](=[O:31])[N:22]1[C:32]1[CH2:33][O:34][C:35](=[O:37])[CH:36]=1
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Agent: C[C@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Product: C[C@H]1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1

Procedure:
The title compound was prepared in two steps from (S)-tert-Butyl 3-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate in an analogous fashion to that described for the preparation of the racemate 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22) immediately above. LC-MS (IE, m/z): 251 (M+1)+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Cu][C:13]#[N:14]>CC(C)=O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: N#C[Cu]
Solvent: CC(C)=O
Product: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Bromo-5-chloro-3-nitropyridine (103) (6.0 g, 25 mmol) was mixed with copper (I) cyanide (4.6 g, 51 mmol) in a 100 mL round-bottom flask having a condensor loosely plugged with cotton was attached. The flask was slowly heated in an oil bath. When the temperature reaches approximately 150° C. (takes 2 h), the reaction mass begins to turn black. When the reaction mass turned completely black, the pressure was reduced to approximately 1 mm Hg by vacuum and the oil bath removed after 30 sec. (If the reaction goes too long, a vigorous reaction ensues, leaving little recoverable product.) The mixture was cooled to room temperature, and the sublimed solid (on the cotton) and reaction mass were treated with hot acetone (100 mL). The resulting mixture was gravity filtered, and the mother liquor rota-evaporated to dryness to yield the crude title compound as a dark brown solid. This solid can be purified by column chromatography using 4:1 hexane-EtOAc (Rf =0.13). Purified 104 was obtained in 60% yield overall, mp 93°-5° C. (Lit., 75° C., Berrie, et al., J. Amer. Chem. Soc.:2042 (1952)); 1H NMR (CDCl3): δ8.62 (d, J=1.5 Hz, 1H), 8.95 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]1=[NH:13])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>O1CCCC1>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]1=[N:13][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCn1c(=N)sc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1c(=NC(=O)C(C)(C)C)sc2ccccc21
Reaction time: 5 h
Yield: 90.1 %

Procedure:
To a solution of 2.0 g of 3-allyl-2-iminobenzothiazole and 1.5 g of triethylamine in 30 ml of tetrahydrofuran was added 1.3 g of pivaloyl chloride dropwise at room temperature under stirring. After reacting for five hours, the reaction mixture was poured into approximately 200 ml of water. The crystals precipitated were collected by filtering to thereby obtain 2.6 g of the objective compound.
Reaction SMILES: [BrH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC>CO.[Pd]>[BrH:1].[BrH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Br
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.4 %

Procedure:
A mixture of 2-benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide (500 mg, 1.19 mmol) and Pd/C (10%, 50 mg, Aldrich) in MeOH (25 mL) was shaken under H2 (20-30 psi, Parr) for 2 h at 25° C. The catalyst was removed by filtration (Celite). The resulting solution was acidified with a dilute solution of HBr in MeOH (pH paper to red). The MeOH was removed in vacuo (rotoevaporator, 35-40° C.) to give a syrup. Ether (45 mL) was added and the resulting mixture was vigorously stirred at 25° C. for 24 h. A yellow suspension was obtained. The solid was collected, washed with ether (3×2 mL) and dried in vacuo (0.005 Torr, 56° C.) to give a beige powder (358 mg, 64%): mp 130° C.; 1H NMR (DMSO-d6) 1.28-1.95 (m, 6 H), 2.69-3.95 (m, 7 H), 4.60-4.55 (m, 2 H), 7.08-7.42 (m, 9 H), 9.60-10.25 (m, 4 H); HRMS Calcd for C20H26N20 : 310.2045. Found: 310.2040.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24]Br)=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26].BrCC1C=CC2C(=CC=CC=2)C=1>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][O:12][CH2:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]([CH3:13])[C:15](=[O:26])[CH:16]=[CH:17]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: COC1(C#CCO)CCOCC1
Agent: BrCc1ccc2ccccc2c1
Product: COC1(/C=C/COCc2ccc3c(ccc(=O)n3C)c2)CCOCC1

Procedure:
The desired compound was prepared according to the method of Example 1, step 4, except substituting 4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in Example 3, for 4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran, and substituting 1,2-dihydro-1-methyl-2-oxo-6-(bromomethyl)quinoline for 2-(bromomethyl)naphthalene. 1H NMR (300 MHz, CDCl3); 7.67 (1H, d, J=9 Hz), 7.52-7.58 (2H, m), 7.35 (1H, d, J=9 Hz), 6.72 (1H, d, J=9 Hz), 5.75 (1H, dt, J=15.5,8 Hz), 5.63 (1H, br d, J=16 Hz), 4.60 (2H, s), 4.10 (2H, dd, J=8,1 Hz), 3.67-3.8 (4H, m), 3.15 (3H, s), 1.72-1.77 (4H, m); MS (M+H)+ =344. Analysis calc'd for C20H25NO4 : C, 69.95; H, 7.34; N, 4.08; Found: C, 69.68; H, 7.16; N, 3.99
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Br:60][C:61]1[CH:62]=[C:63]([CH2:67][NH2:68])[CH:64]=[CH:65][CH:66]=1>ClCCl>[Br:60][C:61]1[CH:62]=[C:63]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[CH:65][CH:66]=1
Reactant: NCc1cccc(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromophenyl)methyl]amine hydrochloride (464 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (962 mg, 1.476 mmol, 73.8% yield) as a white solid. LC-MS m/z 633.6 (M+H)+, 0.97 min (ret time); mp 116-118° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: OCc1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-2(1H)-pyridone (46 mg), 36 mg of benzyl alcohol and 88 mg of triphenylphosphine were dissolved in 2 ml of tetrahydrofuran, 147 mg of a 40% solution of diethylazo dicarboxylate in toluene were added with ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo and purified by a silica gel chromatography (hexane-ethyl acetate system) to give 12 mg of the title compound.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](Cl)=[N:9][OH:10])[CH:2]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:24]=[C:23]([C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=3)[O:10][N:9]=2)[CH:2]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(-c2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(-c4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of biphenyl-3-yl-acetohydroximoyl chloride (60 mg) described in Manufacturing Example 85-1-3 and tetrahydrofuran (3 mL) were added 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and triethylamine (94 μL, 0.68 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound in a crude product Then, the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (32 mg, 62%) as a trifluoroacetic acid salt.