Azzindani/Open_Reaction_Data huggingface dataset:
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].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Yield: 91.5 %

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine (1.0 g, 5.37 mmol), 3-bromo-1-propanol (0.49 ml, 5.37 mmol) and potassium carbonate (1.86 g, 13.4 mmol) was heated at reflux in acetonitrile (10 ml) for 1.5 hours. The mixture was concentrated under reduced pressure and column chromatography of the residue, eluting with 2% methanol/methylene chloride, gave 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (1.2 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N+:27](C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1)([O-:29])=[O:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C2CCc3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc([N+](=O)[O-])c2)O3)nc1

Procedure:
5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-nitrophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 8.32 (s, 1H), 8.23 (d, 1H, J 8.3 Hz), 7.95 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J 15.8, 7.9 Hz), 7.21 (d, 1H, J 9.0 Hz), 6.96-7.03 (m, 3H), 5.35 (d, 1H, J 8.7 Hz), 2.98-3.06 (m, 1H), 2.72-2.79 (m, 1H), 2.26-2.33 (m, 1H), 1.99-2.06 (m, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[CH2:1])[CH:23]=1)[CH3:20]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=Cc1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Methyl triphenylphosphonium bromide (0.99 g; 2.78 mmol) was added to benzene (20 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.8 ml; 2.78 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 8 (0.50 g; 1.86 mmol) in benzene (20 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.21 g of the target compound as pale yellow oily matter (yield: 42.2%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][O:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][O:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])[CH3:3]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: COCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 52.5 %

Procedure:
Following a procedure similar to that described in Example 82(b), but detritylating 2.5 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] with a 25% v/v aqueous solution of acetic acid, 916 mg of the title compound were obtained as crystals, melting at 138°-140° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: CC1(CNc2nc(F)ccc2F)CCOCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCC2(C)CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
To a solution of 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (1.4 g, 5.78 mmol) in MeOH (14 mL) was added sodium methoxide (25 wt. % in MeOH, 7 mL, 30.8 mmol). The mixture was heated in a steel bomb at 135° C. for 3 days. The mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (200 mL), and the resulting precipitate was filtered off and rinsed with water. The solid was dissolved in DCM. The organic solution was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, 20 min, EtOAc/heptane=0/100 for 2 min, then EtOAc/heptane=5/95 to 25/75 over 23 min, EtOAc/heptane=25/75] providing 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as an off-white solid. Yield: 1.22 g. LCMS (m/z): 255.1 [M+H]+; Retention time=0.89 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:17]3[C:18]4[CH2:19][C@H:20]([CH2:29][C:30]([OH:32])=O)[CH2:21][CH2:22][C:23]=4[S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:30]([CH2:29][C@H:20]1[CH2:19][C:18]2[C:17]3[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:14][CH2:13]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][C:23]=2[CH2:22][CH2:21]1)(=[O:32])[NH2:37]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(=O)O)CC4)CC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and containing a solution of 2-[(12R)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1-(9),2(7),3,5-tetraen-12-yl]acetic acid (98 mg, 0.21 mmol, 1.00 equiv) in 4 mL of DMF was added NH4Cl (68 mg, 1.27 mmol, 6.00 equiv), EDCI (61 mg, 0.32 mmol, 1.50 equiv), 4-dimethylaminopyridine (39 mg, 0.32 mmol, 1.50 equiv) and HOBt (43 mg, 0.32 mmol, 1.50 equiv) successively. The resulting solution was stirred overnight at room temperature and quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give tert-butyl N-(4-[[(12R)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (72 mg, 74%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[C:14]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:14]2[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=2)=[N:22]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ncc(Cl)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole (0.49 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.44 g, yield: 69.8%). mp: 74-76° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.2 Hz, 3H), 2.64 (s, 3H), 3.39 (dq, J=5.8 and 7.2 Hz, 2H), 6.00 (s, 1H), 6.90-7.15 (m, 1H), 7.80 (d, J=2.3 Hz, 1H), 8.05 (d, 2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35])#[N:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2].[Pd]>[F:35][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)=[CH:30][C:29]=1[C:27]#[N:28]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc(F)c(C#N)c3)nn3ccnc23)cc1
Temperature: 100 °C

Procedure:
To a vial was added 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine (150 mg, 0.411 mmol) from (1a), 3-cyano-4-fluorophenylboronic acid (74.6 mg, 0.452 mmol), potassium phosphate (174 mg, 0.822 mmol), tris(dibenzylideneacetone)dipalladium (2.0 mg, 0.002 mmol) and 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (CTC-Q-Phos) (5.8 mg, 0.008 mmol) in toluene (2 mL) under nitrogen. The solution was heated to 100° C. for 10 hours. After checking the reaction solution which showed no reaction, more palladium reagent (2.0 mg), ligand (5.8 mg) and boronic acid (74.6 mg) were added. After heating at 100° C. for another 24 hours, the reaction went to completion with no SM left. The crude product mixture was filtered through celite, concentrated in vacuo to provide 2-fluoro-5-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile which was used as is in the next reaction. LC/MS, m/e 450 (M+1). HPLC Rt, 3.60 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[CH:12]=2)=[CH:4][CH:3]=1.[Br:16]Br.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:16][C:12]1[N:11]2[CH2:13][CH2:14][CH2:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(-c2nc3n(c2Br)CCC3)cc1
Reaction time: 0.75 h

Procedure:
A stirred solution of 100 mg (0.50 mmole) of 2-(4- fluorophenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole, prepared as described in Example I, was treated dropwise with a solution of 90 mg (0.56 mmole) of bromine in 0.5 ml of methylene chloride. After 45 minutes, the solution was made basic with 5% aqueous NaOH and dried organics over anhydrous K2CO3. The solvent was removed in vacuo, and the residue was recrystallized from carbon tetrachloride-hexane to give the desired Example V title product, mp 188°-189° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])=[CH:4][CH:3]=1.C(#N)C.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])(=[O:22])[CH3:21]
Reactant: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(Cc1ccc(Cl)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a mixture of N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea (1.3 g) and acetonitrile (10 ml) was added pyridine (1.6 g) and further dropwise acetyl chloride (0.79 g) under ice-cooling. After stirring for 1 hour under ice-cooling, the mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was concentrated and 50 ml of ether and 5 ml of 2N hydrochloric acid were added to the mixture which was then partitioned. The resultant organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 1.6 g of N-acetyl-N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea as a red oil.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[CH:15][N:16]=[C:10]2[CH:9]=1.[F:17][C:18]([F:29])([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O.C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[F:17][C:18]([F:29])([F:28])[CH2:19][N:5]1[N:4]=[N:3][C:7]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[N:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: c1cn2ccc(-c3nn[nH]n3)cc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1nnc(-c2ccn3ccnc3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
Sodium hydride (60 mg, 1.5 mmol) was added to a stirred suspension of 7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (250 mg, 1.3 mmol) in dry DMF (4 ml) under a nitrogen atmosphere. After 1 h, Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (1.16 g, 5 mmol) was added, followed by 18-crown-6 (260 mg, Immol). The reaction mixture was stirred at room temperature for 18 h then quenched with water and extracted with EtOAc (×2). The combined organic extracts were washed with brine (×1), dried (Na2SO4), filtered and the solvent removed in vacuo. Purification via silica column chromatography (0-2% 2M NH3MeOH/CH2Cl2) afforded the product (138 mg). MS: [M+H]+ 269.
Reaction SMILES: B.CSC.[C:5]([CH2:7][C@H:8]([C:10]1[N:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)[OH:9])#[N:6].N.CO.C(Cl)Cl>>[NH2:6][CH2:5][CH2:7][C@H:8]([C:10]1[N:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: B
Agent: N
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: NCC[C@@H](O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
Borane-dimethylsulfide reduction of (R)-benzyl 4-(((6-(2-cyano-1-hydroxyethyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate following the method described in Example 2 gave after flash chromatography purification (30%-40% 7N NH3/MeOH—CH2Cl2 gradient) Example 36 as a colorless oil. Yield (0.27 g, 27%); 1H NMR (400 MHz, CD3OD) δ 7.63 (t, J=8.4 Hz, 1H), 7.38-7.25 (m, 5H), 7.03 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.10 (s, 2H), 4.70-4.62 (m, 1H), 4.21-4.10 (m, 4H), 2.88-2.78 (m, 4H), 2.02-1.70 (m, 5H), 1.34-1.20 (m, 2H); RP-HPLC tR=9.40 min; ESI-MS m/z 400.3 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:13][CH:12]1[C:31]#[N:32])=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH:43][C:26]2[N:25]=[C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:14]3[CH2:15][CH2:16][NH:11][CH:12]([C:31]#[N:32])[CH2:13]3)[CH:29]=[CH:28][N:27]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: N#CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OCc1ccccc1
Product: N#CC1CN(Cc2cccc(-c3ccnc(NCCc4cc(F)cc(F)c4)n3)c2)CCN1

Procedure:
Intermediate 140 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H3O+ of 453. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.37 (d, 1H) 8.19 (s, 1H) 8.15 (d, 1H) 7.68 (d, 1H) 7.60 (t, 1H) 7.37 (d, 1H) 6.94 (d, 2H) 6.85 (m, 1H) 4.60 (s, 2H) 4.05 (dd, 1H) 3.94 (t, 2H) 3.52 (dd, 2H) 3.24 (t, 2H) 3.03 (t, 2H) 2.58 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:5]([CH:6]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C=O)c1OCCCN1CCOCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(C=NCCc2ccccc2)c1OCCCN1CCOCC1
Yield: 85.9 %

Procedure:
3-Methoxy-2-[3-(4-morpholinyl)propoxy]-benzaldehyde (42.5 g) and 18.5 g of phenethylamine are reacted in 150 ml. of toluene following the procedure described in Example 1B, yielding 50.0 g of the title compound, boiling point 229°-234° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:8]3[C:12]([CH2:13][CH2:14][C:15]=2[CH:16]=1)=[N:11][N:10]([C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=3)=[O:4].[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:38])[C:7]2[C:8]3[C:12]([CH2:13][CH2:14][C:15]=2[CH:16]=1)=[N:11][N:10]([C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:9]=3)=[O:4]
Reactant: CI
Reactant: COC(=O)c1cc2c([nH]1)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(n1C)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 7-trityl-1,4,5,7-tetrahydro-1,6,7-triaza-as-indacene-2-carboxylic acid methyl ester XVII (1.1 mmol) in dry DMF (5 mL), NaH (2 eq) was added, the mixture was stirred at rt for 15 min then methyl iodide (2 eq) was added and the mixture was stirred at rt for 2 h. The mixture was poured into aq saturated NaH2PO4, extracted with AcOEt and the organic layer washed with water, dried (Na2SO4) and concentrated. The crude material was triturated with ethanol and filtered. Obtained the title compound (76% yield). ESI (+) MS: m/z 474 (MH+). 1H NMR (300 MHz): 2.48-2.59 (m, 1H), 2.62-2.92 (m, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 6.44 (s, 1H), 7.11-7.31 (m, 15H), 7.61 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]2([C:45]([NH2:47])=O)[CH2:44][CH2:43][CH2:42]2)[CH2:35][CH2:34]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:34][CH2:35][C@H:36]([O:39][CH2:40][C:41]2([C:45]#[N:47])[CH2:44][CH2:43][CH2:42]2)[CH2:37][CH2:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C#N)CCC3)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of 1-[({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)methyl]cyclobutanecarboxamide (0.22 g) and pyridine (0.11 mL) in tetrahydrofuran was added trifluoroacetic acid anhydride (0.093 mL) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 69%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:16]([O:18]C)=[O:17])[C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1.[OH-].[K+].Cl>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1
Reactant: COC(=O)c1cc(C2OCCO2)cnc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C2OCCO2)cnc1C(=O)O
Temperature: 62 °C
Yield: 108.7 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2,3-pyridinedicarboxylic acid, dimethyl ester (2.86 g, 0.011 mol) in methanol is added dropwise to a mixture of potassium hydroxide (1.26 g, 0.022 mol) and methanol. The reaction mixture is heated for 3 hours and 30 minutes at about 62° C., cooled to room temperature, acidified to pH 1 with concentrated hydrochloric acid, filtered through diatomaceous earth and the filtrate is concentrated in vacuo to yield the title compound as a pale yellow powder (2.86 g, 100%), identified by IR and NMR spectral analyses.