Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CO>[C@H:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: [H][H]
Solvent: CO
Product: O[C@@H]1CCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl(R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.66 g (5.0 mmol) of 1-indanone and 4.4 ml of methanol were added thereto, then hydrogen gas was charged to 3.0 MPa. Subsequently, the mixture was stirred for 20 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-1-indanol was obtained at a conversion rate of 58.6% with an optical purity of 97.8% ee.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([O:25][CH3:26])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([O:25][CH3:26])[N:16]=1
Reactant: CC(C)N
Reactant: COc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 86.1 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methoxypyrimidine (11.5 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 45 min. Purification was conducted by a column chromatography to obtain a yellow solid (10.9 g) in a yield of 86.1%. 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 4.42 (m, 1H), 4.01 (s, 3H), 1.23 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[N:14]=[C:15]([CH2:18][CH3:19])[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]=1)[CH3:19]
Reactant: CCc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(COc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.6 %

Procedure:
A mixture of 4-nitrophenol (5.48 g), 4-chloromethyl-2-ethyl-1,3-thiazole (7.40 g), potassium carbonate (5.45 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-4-[(4-nitrophenoxy)methyl]-1,3-thiazole as colorless crystals (3.60 g, yield 35%) from a fraction eluted with hexane-ethyl acetate (4:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 79-80° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([CH:12]=[C:13]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[C:14]([F:17])([F:16])[F:15])(=[O:11])=[O:10].[CH2:26]([N:33]([CH2:37][Si](C)(C)C)[CH2:34]OC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[CH2:37][CH:12]([S:9]([CH3:8])(=[O:11])=[O:10])[C:13]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)([C:14]([F:17])([F:15])[F:16])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CS(=O)(=O)C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Trifluoroacetic acid (6 μL, 78 μmol) was added to 2-(3,5-Dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl methyl sulfone (500 mg, 1.57 mmol) in toluene (3 mL). N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (558 mg, 2.35 mmol) in toluene (2 mL) was added at room temperature over 10 minutes. The reaction mixture was stirred for two hours and then additional N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (74.4 mg, 313 μmol) was added. The reaction mixture was stirred for additional two hours and then left standing over night. Water was added and after stirring for a while the phases were separated and the aqueous phase was extracted with toluene. The combined organic phases were dried over sodium sulfate and evaporated. The crude product is taken up in warm iso-propanol (1 mL) and 10% hydrochloric acid (0.5 mL) and a drop of methanol was added. The formed crystals were filtered off. The hydrochloride was suspended in water and sodium hydroxide and tert-buthyl methylether was added. The organic phase was separated and the aqueous phase was extracted with tert-buthyl methylether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. This procedure yielded 1-benzyl-3-(3,5-dichlorophenyl)-4-(methylsulfonyl)-3-(trifluoromethyl)pyrrolidine (302 mg, 99% purity, 42% yield).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:26]=[CH:25][C:5]3[N:6]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[O:19][C:18](=[O:20])[NH:17][N:16]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:30][N:29]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)n1c(-c2ccccc2-c2n[nH]c(=O)o2)nc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2ccccc2-c2n[nH]c(=O)o2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a sealed vial is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3H-[1,3,4]oxadiazol-2-one (40 mg, 0.097 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (25 mg, 0.113 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8 mg, 0.011 mmol) and 2M aq. Na2CO3 (0.2 ml, 0.4 mmol). The reaction mixture is heated under Argon at 100° C. for 6 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-10% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford the title compound (4 mg, 10%) as a pale-white solid. LCMS (ESMS): m/z 428.87 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1C(=O)N([Br:23])C(=O)C1>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:23][CH2:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cc1cc2ccccc2c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1cc2ccccc2c2ccccc12
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A mixture of 9-methylphenanthrene (14.2 g, 74 mmol), benzoyl peroxide (40 mg, 0.16 mmol) and NBS (13.3 g, 74.6 mmol) in 210 mL of benzene was refluxed for 5 h. The reaction mixture was cooled to 0° C. and the succinimide precipitated was removed by filtration. The filtrate was washed by 15% NaOH, dried over MgSO4 and concentrated to yield 18 g of product which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[NH4+].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(Cl)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1c[n+]([O-])c(C)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The above 3-chloro-2,5-dimethylpyridine 1-oxide (1.20 g) was dissolved in concentrated sulfuric acid (6 mL), and a mixture of fuming nitric acid (9.5 mL) and fuming sulfuric acid (5.5 mL) was added dropwise over 25 minutes. After stirring in that state for 30 minutes, the mixture was stirred at 90° C. for two hours. The reaction solution was left to cool, and then introduced into ice water and neutralized with ammonium carbonate with stirring at room temperature. The insoluble matter was separated off by filtration, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (1.11 g, 72%) as a solid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37]([NH:36][CH2:34][CH3:35])=[O:38])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, ethyl isocyanate (0.16 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCL (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3CN 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.2 g, 30%) as a white solid: mp 173-175° C.; 1H NMR (DMSO-d6). δ d 11.13 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=6.1 Hz, 1H), 6.11 (t, J=5.55 Hz, 1H), 5.18-5.11 (dd, J=5.4 and 12.6 Hz, 1H), 4.63 (d, J=6.1 Hz, 2H), 3.07-2.83 (m, 3H), 2.64-2.49 (m, 2H), 2.08-2.04 (m, 1H), 0.99 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.58, 167.03, 157.93, 141.15, 134.61, 133.37, 131.49, 126.96, 121.61, 48.83, 38.71, 34.17, 30.92, 21.98, 15.58; Anal. Calcd. For C17H18N4O5+0.14H2O: C, 56.58; H, 5.11; N, 15.53. Found: C, 56.56; H, 5.05; N, 15.28.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1)([CH3:30])[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Yield: 33 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine (0.1 g, 0.25 mmol), 2-isopropyl-1H-benzoimidazole 0.078 g, 0.49 mmol), Xphos (0.024g, 0.049 mmol), Pd2(dba)3 (0.012 g, 0.012 mmol) and Cs2CO3 (0.159 g, 0.49 mmol) in dioxane (1.5 mL) was subjected to microwave irradiation at 145° C. for 45 min. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95) to give 470 as a yellow solid (0.044 g, 34%). LCMS (Method I): RT=2.88 min, [M+H]+ 534.2. 1H NMR (400 MHz, DMSO-d): δ 7.89-7.85 (m, 1 H); 7.66-7.61 (m, 1 H); 7.28-7.22 (m, 2 H); 4.36-4.30 (m, 4 H); 4.00 (s, 2 H); 3.97-3.89 (m, 1 H); 3.85 (dd, J=11.2, 4.0 Hz, 2 H); 3.79 (t, J=4.6 Hz, 4 H); 3.49 (t, J=7.3 Hz, 2 H); 3.39-3.35 (m, 2 H); 3.07 (t, J=6.8 Hz, 2 H); 2.27-2.21 (m, 1 H); 1.73-1.64 (m, 1 H); 1.52 (d, J=13.1 Hz, 2 H); 1.33 (dd, J=6.8, 4.0 Hz, 6 H); 1.10 (td, J=12.2, 4.6 Hz, 2 H)
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CC(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a slurry of 2-amino-3-bromobenzoic acid (Aldrich; 1.00 g, 4.63 mmol) in 10 mL EtOAc in an ice bath was added 1-propanephosphonic acid cyclic anhydride (50 wt % in EtOAc; Matrix Scientific; 3.00 mL, 5.09 mmol) followed by isopropylamine (1.19 mL, 13.89 mmol). The ice bath was removed and the solution stirred rapidly at RT. A precipitate formed. After 30 min, the reaction was judged complete. The reaction was partitioned between sat'd aq. NaHCO3 and EtOAc. The organic layer was washed with sat'd aq. NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-N-isopropylbenzamide (1.00 g, 3.89 mmol, 84% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (2H, dd, J=7.9, 1.5 Hz), 7.25 (1H, d, J=1.4 Hz), 6.53 (2H, t, J=7.8 Hz), 5.72-6.15 (3H, m), 4.15-4.33 (1H, m), 1.27 (7H, d, J=6.7 Hz). m/z (ESI, +ve) 257.0/259.0 (M+H)+.
Reaction SMILES: [OH-].[K+].CC(C)(C)C([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]2([CH3:24])[CH3:23])[N:9]=1)=O.Cl>CO>[CH3:23][C:16]1([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([CH3:21])([CH3:22])[N:15]1[CH2:14][C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CN2C(C)(C)CCCC2(C)C)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCC(C)(C)N1Cc1cccc(N)n1
Temperature: 25 °C

Procedure:
KOH (1.68 g, 33.5 mmol) in MeOH (100 mL) was added to 2,2-dimethyl-N-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-propionamide (150 mg, 0.45 mmol) and the resulting mixture was heated at reflux for 12 h. After cooling to 25° C., the mixture was neutralized to pH 7–8 with concentrated HCl and extracted with CHCl3 (3×75 mL). The organics were combined and dried over MgSO4. Concentration in vacuo gave a pale yellow solid. MS m/z: 247.7 (M+). Calc'd for C15H25N3-247.38.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[N:20]=[CH:21][CH:22]=[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.I[Si](C)(C)C>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[N:20]=[CH:21][CH:22]=[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(C(=O)OC(C)(C)C)ccnn23)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccnn2c(-c3ccc(N)cc3)nnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To a solution of tert-butyl 3-(4-(tert-butoxycarbonylamino)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (66E) (100 mg, 0.24 mmol) in CH2Cl2 (4 mL) was added iodotrimethylsilane (86 μL, 0.6 mmol) dropwise. After addition, the reaction mixture was stirred at room temperature for 10 min. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was partitioned between CH2Cl2 and water, then the separated CH2Cl2 layer was washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl, dried (anhydrous Na2SO4), and concentrated. The obtained crude residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (50-100%) in hexanes to afford 60 mg (79%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=2.03 min, [M+H]+=312.3.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=[C:34]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([BH3-])#N.[Na+]>C(O)C>[C:35]([C@@H:34]([NH:18][C@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11])[CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 g (0.0268 mol) of tert-butyl Nε -benzyloxycarbonyllysinate hydrochloride are dissolved in 150 cm3 of anhydrous ethanol; 2.71 g (0.0268 mol) of triethylamine, 20.6 g (0.1 mol) of ethyl 2-oxo-4-phenylbutyrate and 20 g of 4Å molecular sieve are added. The mixture is stirred for one hour at 20° C. A solution of 1.68 g (0.0268 mol) of sodium cyanoborohydride in 20 cm3 of ethanol is then added in the course of 4 hours, after which stirring is continued for 18 hours at 20° C. The mixture is filtered and taken to dryness, the residue is redissolved in 200 cm3 of ethyl acetate and the solution is then washed twice with 100 cm3 of a 10% strength aqueous citric acid solution and then with water until the washing liquors are neutral. The mixture is dried over magnesium sulfate and evaporated. 28.7 g of an oil are collected, and this is purified by chromatography on silica gel (eluent: methylene chloride/acetone 95:5). After the removal of impurities and then the (S, R) isomer, 4.1 g of tert-butyl (S)-Nα -[(S)-1-carbethoxy-3-phenylpropyl]-Nε -benzyloxycarbonyllysinate are collected, and used without further treatment in the following stage.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4]1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[C:11]1([CH2:10][N:9]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:8]2[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4][C@H:3]2[O:2][CH3:1])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OC)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](OC)C1
Reaction time: 240 h
Yield: 64 %

Procedure:
A mixture of 183.4 parts of ethyl cis-3-methoxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate, 144 parts of (chloromethyl)benzene, 85 parts of sodium carbonate and 720 parts of methylbenzene was stirred for 10 days at reflux temperature. The reaction mixture was filtered and the filtrate was washed three times with 400 parts of water, dried, filtered and evaporated. Petroleumether was added. The whole was cooled whereupon the product solidified. It was filtered off and crystallized from petroleumether. The product was filtered off and dried in vacuo at 40° C., yielding 155 parts (64%) of ethyl cis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate; mp. 95.2° C. (int. 46).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:12]=[C:13]([NH2:25])[C:14]3[N:15]([N:17]=[C:18]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:16]=2)[CH:6]=1)C.[Li+].[OH-]>CO.C1COCC1>[NH2:25][C:13]1[C:14]2[N:15]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:16]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:26])=[O:3])[N:12]=1
Reactant: CCOC(=O)c1cccc(-c2cn3nc(-c4ccco4)nc3c(N)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(-c2cccc(C(=O)O)c2)cn2nc(-c3ccco3)nc12
Temperature: 70 °C

Procedure:
A mixture containing 3-(8-amino-2-furan-2yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-benzoic acid ethyl ester (100 mg; see Ex. 141 below, which was prepared according to Example 4 above), LiOH (2 M, 1 mL), and MeOH (a few drops) in THF (10 mL) was heated (at around 70° C.) for 1 hour. The solvent was removed in vacuo, and the residue was taken up in water and acidified, resulting in a precipitate, which was filtered off as the desired product with an appearance of a light brown solid (60 mg, 65 %). 1H NMR (300 MHz, DMSO-d6) δ 6.76 (dd, J=3.4, 1.8Hz, 1H), 7.18 (dd, J=3.4, 0.8, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.68 (br. s, 2H), 7.96 (dd, J=1.8, 0.8 Hz, 1H), 8.00 (dt, J=7.8, 1.8 Hz, 1H), 8.30 (dt, J=7.8, 1.8 Hz, 1H), 8.72 (t, J=1.8, 1H), 8.91 (s, 1H), 13.09 (br. s, 1 H). MS: m/z 322 [M+H]+.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[N+](C1C=CC=CC=1C=O)([O-])=O.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Cinnamyl alcohol (270 mg, 2.0 mmol) was dissolved in benzene (1 mL), added with aluminum isopropoxide (40 mg, 0.1 eq, 0.20 mmol) and 2-nitrobenzaldehyde (390 mg, 1.3 eq, 2.6 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate and made acidic with addition of 2 N hydrochloric acid, and then the organic layer was separated. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 260 mg (yield: 97%) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(N(CC)CC)C.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(SN2C(=O)CCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
3,5-Dimethylthiophenol (2.76 g, 0.02 mol) was added by a syringe to an ice cooled mixture of N-chlorosuccinimide (3.34 g, 0.025 mol) and anhydrous dichloromethane (30 mL) under argon atmosphere. After 1 hour, N-chlorosuccinimide (0.4 g, 0.003 mol) was added, then reaction was stirred for 2.5 hours. Triethylamine (3.9 mL, 0.028 mol) was added while stirring for 15 minutes, then dichloromethane and 1N HCl were added. After shaking, organic layer was dried, concentrated to a small volume and passed through a Celite® column. After evaporation of the solvent, the residue was triturated with diethyl ether to give 3.0 g (64%) of title compound, mp 131-134° C. (from diethyl ether).