Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][OH:18])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O

Procedure:
A solution of trans-{1-[2-(4-fluorophenyl)ethyl]-4-methylpiperidin-3-yl}-methanol (251 mg, 1.0 mmol) in dichloromethane (10 mL) was treated with triethylamine (280 μL, 2.0 mmol) and stirred on an ice-acetone bath. Methanesulfonyl chloride (85 μL, 1.1 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 1.5 hours. The solution was concentrated under vacuum, and the residue was taken up in ethyl acetate and filtered. The filtrate was concentrated under vacuum to provide an orange gum (342 mg, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 4.30 (dd, J=10, 3 Hz, 1H), 4.18 (dd, J=10, 7 Hz, 1H), 3.13 (dm, J=10 Hz, 1H), 3.02 (s+m, 4H), 2.83 (m, 2H), 2.66 (m, 2H), 2.07 (m, 2H), 1.76 (m, 2H), 1.43 (m, 2H), 1.02 (d, J=6, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(n3)c(-c3cccnc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 45 °C
Yield: 50.2 %

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (6 mg, 0.01 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (100 μL). The reaction mixture was heated at 45° C. overnight. The reaction mixture was concentrated, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC (10-100% ACN/H2O+0.1% TFA) to give the product (3 mg). 1H NMR (400 MHz, CD3OD) δ 9.70 (bs, 1H), 8.97 (d, J=3.8 Hz, 1H), 8.60 (bs, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.84-7.56 (m, 6H), 5.24 (s, 1H), 4.13 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H). LCMS-ESI+: calc'd for C32H28ClN5O3S: 598.2 (M+H+); Found: 598.2 (M+H+).
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[ClH:14].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(C)cc1Br
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Cl)c(C)cc1Br
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a cooled solution (15° C.) of methyl 5-amino-2-bromo-4-methylbenzoate (122 g, 0.5 mol) in 1,4-dioxane (633 mL), was added conc. hydrochloric acid (550 mL). After the mixture was cooled to 5° C., a solution of sodium nitrite (35.53 g, 0.515 mol) in 83 mL of H2O was added dropwise at such a rate that the reaction temperature was kept below 0° C. After being stirred at 0° C. for 2 hours, the reaction mixture was added slowly to a flask containing copper (I) chloride (59.4 g, 0.6 mol) and conc. hydrochloric acid (275 mL). It was stirred for 40 min, at which time TLC demonstrated that the reaction was complete. The reaction mixture was poured over ice water (2 L) and then filtered. The filter cake was dissolved in ethyl acetate (1.5 L). The organic layer was washed with brine (3×500 mL), dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as light yellow crystals. Yield: 120 g (92.6%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (s, 1H), 7.54 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H); MS ESI (m/z) 262 (M)+, calc. 262.
Reaction SMILES: C([NH:8][C@@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.[NH4+].OC1C2N=N[NH:30]C=2C=CC=1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[NH2:8][C@@H:9]([C:20]([NH2:30])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Boc-D-Tryptophan (9) (1 equiv.; 2.75 mmol; 1.00 g), hydroxybenzotriazole ammonium salt (2 equiv.; 5.50 mmol; 924 mg) and diisopropylcarbodiimide (DIC) (1.1 equiv.; 3.03 mmol; 382 mg; 454 μl) were dissolved in dimethylformamide (DMF) which had been dried over molecular sieves, and the solution was stirred at room temperature for 18 h. The solvent was then removed on a rotary evaporator under reduced pressure, and the residue was taken up in ethyl acetate. Insoluble residues were filtered off, and the organic phase was then washed (1×1 M KHSO4 solution, 2× saturated aqueous sodium carbonate solution, 1× saturated aqueous sodium chloride solution), dried over sodium sulfate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]4[O:24][CH2:23][CH2:22][O:18]4)[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2ccc(C=Cc3cccc(C4OCCO4)c3)nc2c1

Procedure:
A mixture of 3-(2-(7-chloroquinolin-2-yl)ethenyl)benzaldehyde (step 1) (938 mg, 3.19 mmoles), ethylene glycol (200 μL, 1.15 equiv.), p-toluenesulfonic acid (296 mg, 0.5 equiv.) and toluene (1.5 mL) was heated at reflux overnight. 25% aqueous NH4OAc was then added and the mixture extracted with EtOAc. Flash chromatography of the residue on silica with EtOAc:hexane 20:80 afforded the title compound.
Reaction SMILES: C(OC([N:8]([C:11]1([C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10])=O)(C)(C)C.C(N(CC)CC)C.F[C:27]1[C:36]([CH3:37])=[C:35]2[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:29][CH:28]=1>CS(C)=O>[CH2:9]([NH:8][C:11]1([C@@H:14]2[CH2:18][CH2:17][N:16]([C:27]3[C:36]([CH3:37])=[C:35]4[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]4[C@@H:38]4[CH2:40][C@@H:39]4[F:41])=[CH:29][CH:28]=3)[CH2:15]2)[CH2:12][CH2:13]1)[CH3:10]
Reactant: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]pyrrolidine (2.16 g, 8.40 mmol) and triethylamine (4 ml) to dried dimethyl sulfoxide (10 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.95 g, 7.00 mmol) was added thereto and heated under reflux in an oil bath of 100° C. for 51 hour under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (150 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (10 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (20 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (100 ml×5), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (150 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from ethanol and then dried under a reduced pressure. 1.61 g (55%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:31][O:32][NH2:33]>>[CH3:31][O:32][N:33]=[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CON
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)c1ccccc1
Agent: Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(=NOC)c1ccccc1

Procedure:
By the general method described in Part F of Example 30, 4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one was reacted with O-methylhydroxylamine hydrochloride to provide 4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one O-methyloxime) in about an 8.7 to 1 mixture of E and Z isomers as a yellow solid after recrystallization from methanol, mp 198-200° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(I)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 86 %

Procedure:
A solution of 5 g (19 mmol) of (4-iodo-phenyl)-acetic acid in 50 mL of methanol (MeOH) was added dropwise 3.5 mL (48 mmol) of thionyl chloride (SOCl2), and the resulting mixture was stirred at rt for 36 h, after which time analysis by thin layer chromatography (TLC) indicated product formation. The mixture was concentrated to give 4.5 g (86% yield) of (4-iodo-phenyl)-acetic acid methyl ester as a pale beige oil as indicated by 1H NMR.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]=[CH:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)=[O:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4].[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].C([SiH](CC)CC)C>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[N:25]=[CH:26][NH:27][CH:28]=4)=[O:23])=[CH:19][CH:20]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)cc3)nc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4c[nH]cn4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (46 mg, 0.06 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with triethylsilane (20 μL, 0.12 mmol) and then concentrated in vacuo. The resulting residue was purified by HPLC (20–95% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 20 min). Fractions with the desired product were freeze dried to afford 1H-imidazole-4-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide; compound with trifluoro-acetic acid (27.8 mg, 74%) as a white solid: EI-HRMS m/e calcd for C27H26N7O3F (M+) 515.2081, found 515.2083.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC[O:9][C:10]([CH3:12])=[O:11]>CC(O)=O>[CH:3]1([CH2:6][CH2:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][CH2:12][C:10]([OH:9])=[O:11])[CH2:2][CH2:1][CH2:6][CH2:5][CH2:4]1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CC/C=C\CCCC1CCCCC1

Procedure:
Rf =0.6 in 1:1 hexane-EtOAc with 0.5% AcOH.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:14](=[O:15])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:32]3[CH2:33][C@@H:28]4[CH2:34][C@H:31]3[CH2:30][O:29]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:23]([F:26])([F:25])[F:24]
Reactant: Cc1ccncc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccncc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 120 °C
Yield: 74.2 %

Procedure:
140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 126 μl (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120° C. in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[C:5]([O:19][CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:5]1[C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(OC)cccc12
Reactant: CN(C)C=O
Product: COc1cccc2c1[nH]c(=O)n1c(=O)[nH]nc21
Temperature: 25 °C

Procedure:
1.02 g (0.0036 mol) of ethyl 2-hydroxy-8-methoxy-quinazolin-4-yl-carbazate in 65 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from methanol. Yield: 0.52 g (61%) of 7-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 308°-310° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)NCCN1CCOCC1
Yield: 34 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and 4-(2-aminoethyl)morpholine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (22 mg, Yield 34%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:33]([C@@H:40]1[CH2:44][O:43][C:42](=[O:45])[NH:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Li]CCCC>C1COCC1>[CH2:33]([C@@H:40]1[CH2:44][O:43][C:42](=[O:45])[N:41]1[C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)O)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a stirred solution of (2E)-3-[3-(tert-butoxycarbonyl)phenyl]prop-2-enoic acid from the previous step (0.186 g, 0.749 mmol) in THF (3 mL) was added triethylamine (0.110 mL, 0.787 mmol) and the mixture was cooled to −20° C. Pivaloyl chloride (0.0969 mL, 0.787 mmol) was added and then the reaction mixture was stirred at −20° C. for 15 min, warmed to 0° C. and stirred for 40 min. Meanwhile, to a cooled (−78° C.) solution of (R)-4-benzyl-2-oxazolidinone (0.305 g, 1.72 mmol) in THF (5 mL), was added nBuLi (1.1 mL, 1.6M in hexanes) dropwise and the mixture was stirred for 30 min. The slurry was warmed to 0° C. and added via cannula into the anion solution. After one hour, the reaction was quenched by the addition of 10 mL 20% aqueous NH4Cl solution, warmed to room temperature and extracted with 2×50 mL ether. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure, and chromatographed on a 4″ 25 mm SiO2 column using 18% EtOAc:hexanes. The clean fractions were combined and the solvent was removed under reduced pressure to give tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate as an oil (0.273 g, 89%). TLC Rf=0.3 (1:4 EtOAc:hexanes, UV visualization); HPLC RT=2.9 min, method B; M+H=408.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[C:19]([NH:32][NH2:33])(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([NH:33][NH:32][C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:12])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CCCCCCCCCCCC(=O)NN
Solvent: CO
Product: CCCCCCCCCCCC(=O)NNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
Into a 3-necked 300 ml flask was introduced a 60.9% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol (21.0 g, 0.05 mole), lauric acid hydrazide (13.5 g) and 150 ml of anhydrous methanol. The flask was equipped with a thermometer, a magnetic stirrer and a Dean Stark trap with a reflux condenser. The reaction mixture was heated to reflux and the methanol was slowly distilled off through the Dean Stark trap. The disappearance of the starting materials and the formation of the products were monitored by liquid chromatography. After 6 hours at reflux and the removal of 110 ml of methanol, the liquid chromatograph scans indicated the reaction was essentially complete. The reaction mixture was filtered hot and the filtrate was stripped to dryness on a rotating evaporator under reduced pressure. The residue was a white powder weighing 16.6 g and had a melting range of 80°-84° C. An infrared scan (nujol mull) of the product contained strong carbonyl bands at 1655, 1580 and 1490 cm-1.
Reaction SMILES: [BH4-].[Na+].[H][H].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH:15]([CH2:41][N+:42]([O-])=O)[CH2:16][C:17]1[N:21]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[N:19][N:18]=1>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:42][CH2:41][CH:15]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:6]=1[CH3:5])[NH2:12])[CH2:16][C:17]1[N:21]([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]=[N:19][N:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N)cc1C(CN)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Adapting a literature known protocol (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2 6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of 5-[2-(2-methyl-5-nitro-phenyl)-3-nitro-propyl]-1-trityl-tetrazole (20b) (5.35 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS to completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are evaporated to dryness under reduced pressure using a rotary evaporator. The crude material (20c) is used directly in the next step without further isolation and purification.
Reaction SMILES: C([Li])CCC.[NH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[N:15]=[C:16](S(C)(=O)=O)[N:17]=[N:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][C:14]1[N:15]=[C:16]([NH:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:17]=[N:18][C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc(S(C)(=O)=O)nnc1-c1ccccc1
Reactant: NN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(NN2CCCCC2)nnc1-c1ccccc1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
n-Butyllithium (25 g/250 ml solution in hexane) (28.5 ml) was added dropwise to a stirred solution of N-aminopiperidine (4.12 g) in tetrahydrofurane (40 ml) at -78° C. and the stirring was continued for 2 hours at room temperature. A solution of 5-methyl-3-methylsulfonyl-6-phenyl-1,2,4-triazine (5 g) in tetrahydrofuran (100 ml) was added dropwise to the above obtained solution at -78° C. in 70 minutes with stirring and the stirring was continued for 30 minutes at the same temperature. The reaction mixture was washed with water and brine, and then extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated. The resulting residue was dissolved in chloroform and extracted with an aqueous solution of 6N-hydrochloric acid. The extract was made alkaline with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and evaporated. Thus obtained crude product (3.82 g) was purified by chromatography on silica gel (100 g) using a mixture of benzene and ethyl acetate (2:1) as an eluent and recrystallized from diisopropyl ether to give crystals of 5-methyl-6-phenyl-3-piperidinoamino-1,2,4-triazine (2.25 g).