Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)N1CCC(Oc2ccc(O)cc2)CC1
Yield: 83.5 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[NH:5][CH:6]=[N:7]2.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[NH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]cnc2cccc(Cl)c12
Agent: O=S(=O)(O)O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Reaction time: 1 h

Procedure:
A solution of the above quinazolinone (1.26 g, 7.0 mmol) in conc. H2SO4 (7 mL) was cooled to −20° C., and 90% HNO3 (0.49 g, 7.0 mmol) was added with stirring. Stirring continued for 1 h at −20° C., and 2 h at room temperature. The mixture was poured onto ice, filtered, washed with water and dried to give 5-chloro-6-nitroquinazolin-4-one, along with the 8-nitro isomer in a 4:1 ratio. Three recrystallizations from EtOH gave the product as a 6:1 ratio of isomers (0.85 g).
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[C:12]([CH3:18])=[C:13](N)[CH:14]=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:32]([O:35]C(=O)C)(=[O:34])[CH3:33]>CCCCC>[C:32]([O:35][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([Br:10])[C:12]=1[CH3:18])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cncc1Br
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=O)Oc1cncc(Br)c1C
Temperature: -15 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a flask containing boron trifluoride etherate (0.35 mL, 2.8 mmol) at −15° C. was added a solution of 5-bromo-4-methylpyridin-3-amine (249.0 mg, 1.331 mmol) in 1,2-dimethoxyethane (2.0 mL, 19 mmol). Tert-butyl nitrite (0.20 mL, 1.7 mmol) was then added dropwise and the reaction mixture stirred at −15° C. for one hour. 3 mL pentane was then added and the solid material collected by vacuum filtration. The solid material was dissolved in acetic anhydride (2.0 mL, 21 mmol) and stirred at 100° C. for one hour. The solvent was evaporated in vacuo, and the residue then suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-40% ethyl acetate in heptanes) to yield 117.7 mg (38%) of 5-bromo-4-methylpyridin-3-yl acetate. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.35 (s, 1H), 2.37 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)[OH:4].[C:20]1([C@H:26]([N:28]=[C:29]=[O:30])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1C=CC=CC=1.CCOCC>[O:11]([C:7]1[N:6]=[C:5]([CH:3]([O:4][C:29](=[O:30])[NH:28][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(NC(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F)c1ccccc1

Procedure:
A stirred solution of 2.40 g (8.91 mmol) of α-trifluoromethyl-6-phenoxy-2-pyridinemethanol, 1.38 g (9.36 mmol) of (R)-(+)-1-phenylethyl isocyanate, and 22 mg (0.18 mmol) of 4-dimethylaminopyridine in 9 ml of benzene under a nitrogen atmosphere was heated at 50° C. for 17 hours. The reaction mixture was then diluted with 150 ml of ether and washed with 25 ml of 1N aqueous HCl, 25 ml of saturated aqueous NaHCO3, and 25 ml of saturated aqueous NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Repeated chromatography of the residue on silica gel with benzene afforded first 1.77 g (48%) of the [R-(R*,R*)] diastereomer: Rf =0.10 (SiO2, benzene); 1H NMR (CDCl3) δ 1.52 (d, 6.8 Hz, 3H), 4.83 (quintet, 7.1 Hz, 1H), 6.01 (q, 6.1 Hz, 1H), 6.83 (d, 8.2 Hz, 1H), 7.11-7.37 (br m, 12H), and 7.68 (t, 7.8 Hz, 1H); and then 1.77 g (48%) of the [S-(R*,S*)] diastereomer: Rf =0.09 (SiO2, benzene); 1H NMR (CDCl3) δ 1.47 (d, 6.8 Hz, 3H), 4.80 (quintet, 7.0 Hz, 1H), 5.98 (q, 6.9 Hz, 1H), 6.86 (d, 8.3 Hz, 1H), 7.13-7.42 (br m, 12H), and 7.72 (t, 7.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH3:25].C(OC1C=C(C2[C@H]3[C@H](CC=CC3)C(=O)NN=2)C=CC=1OC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][CH2:24][CH3:25])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CCCBr
Agent: CCOc1cc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)ccc1OC
Product: CCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and 1-bromopropane as described for compound 6. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 95-96° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10](=[O:12])[CH3:11].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)NCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCc1nccn1COCC[Si](C)(C)C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 0.08 g of sodium hydride (60% oily) was added to a solution of 0.31 g of N-(imidazol-2-ylmethyl)acetamide in N,N-dimethylformamide (10 ml). After stirring for 15 minutes, a solution of 0.35 ml of 2-(trimethylsilyl)ethoxymethyl chloride in N,N-dimethylformamide (1 ml) was dropped thereinto and the resulting mixture was stirred at room temperature for additional 16 hours. Then the reaction mixture was distributed into water and ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.16 g of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Reactant: Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(Cl)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.042 g, 0.22 mmol) and 4-chloroaniline (0.028 g, 0.22 mmol) in chloroform (1.5 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][CH2:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][CH2:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 51 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (Example 23, 0.717 g.) and HDPhe-Leu-NleNH2 hydrochloride salt (0.585 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-DPhe-Leu-NleNH2 in 51% yield. De-t-butoxycarbonylation of BocPro-Dphe-Dphe-Leu-NleNH2 (0.500 g.) using hydrogen chloride in acetic acid gave HPro-DPhe-Phe-DPhe-Leu-NleNH2, which was isolated as the amorphous white solid hydrochloride salt trihydrate in 36% yield.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.Cl.CCO.[OH-].[Na+:37]>O>[Na+:37].[Na+:37].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 70 °C

Procedure:
N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid from example 7 is dissolved in water (3.8 mL) and sodium hydroxide 1N (2.2 mL). The pH of the mixture is adjusted to 7.5-8.5, by the addition of hydrochloride acid 1N. The solution is heated at 70° C. and ethanol absolute (40 mL) is added to the mixture. The solution is allowed to cool down slowly to room temperature. The slurry is filtered and washed with a mixture of ethanol absolute and water (4:1). The resulting white solid is dried in the oven at 50° C. under vacuum over 18 h.
Reaction SMILES: [C:1]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9]O[C:7]=1[CH3:13])([O:3][CH2:4][CH3:5])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1c(C)occc1=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)ccc1=O

Procedure:
The crude 3-carboethoxy-2-methylpyr-4-one isolated from the previous reaction is dissolved in 50 ml toluene. 2.4 g of aniline and 400 mg of p-toluenesulfonic acid monohydrate are added and the mixture refluxed for 1 hour. Evaporation of the solvent leaves 6.3 g of crude 3-carboethoxy-N-phenyl-2-methylpyrid-4-one.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+].C[OH:19].O>CCO>[CH3:15][O:16][C:4]1[CH:5]=[CH:6][C:7]2[O:19][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:1](=[O:8])[C:2]=2[CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2oc3ccccc3c(=O)c2c1
Yield: 91.6 %

Procedure:
The benzophenone intermediate was then stirred in EtOH (400 ml) at room temperature and treated with a solution of NaOMe in MeOH (25 wt. %, 45.72 ml, 0.2 mole). The color of the reaction mixture changed to burgundy right away. The reaction mixture was brought to reflux for 1 hr and 20 min, TLC showed that the reaction was complete. After brief cooling, water (500 ml) was added while the mixture was still warm and a yellow powder precipitated. The suspension was stored in refrigerator overnight. The solid was filtered on a Buchner funnel and washed with cold water. 2-Methoxy-9H-xanthen-9-one 1 (20.7 g, 91.6%) was obtained as a light yellow powder: m.p. 128-130° C.; 1H NMR (CDCl3): delta 8.33 (1H, dd, J=7.9, 1.8 Hz), 7.67-7.72 (2H, m), 7.47 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=9.2 Hz), 7.35 (1H, m), 7.31 (1H, dd, J=9.2, 3.1 Hz) and 3.90 (3H, s); 1R (CHCl3): 2998, 1635, 1610, 1480, 1463, 1430, 1313, 1266, 1140, 1108, 1038, 852 and 823 cm-1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)[CH3:33]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (122 mg, 0.29 mmol) was taken up in DMF (2.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (152 μl, 0.87 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (165 mg, 0.434 mmol), and ethanamine hydrochloride (26.0 mg, 0.318 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 135 mg (85%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.82 (s, 1H), 9.83 (br. s., 1H), 8.25 (t, J=5.6 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 6.94-7.12 (m, 3H), 4.59 (d, J=13.1 Hz, 1H), 4.27 (br. s., 2H), 3.85-4.10 (m, 3H), 3.43 (d, J=10.4 Hz, 2H), 3.21-3.30 (m, 2H), 2.95-3.19 (m, 4H), 2.61-2.72 (m, 1H), 2.05 (d, J=11.8 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.1 Hz, 1H), 1.31-1.62 (m, 3H), 1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C23H27N5O3, 449; found, 449. MP: 232.6° C.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:23]2[C:31]3[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=3)[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:24]=2)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([F:42])[CH:11]=1.CI>O1CCCC1.ClCCl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:23]2[C:31]3[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=3)[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:24]=2)[CH:17]([CH3:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([F:42])[CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1F)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1F)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.55 ml (7.10 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran were introduced into 40 ml of absolute tetrahydrofuran at −78° C., a solution of 3.00 g (5.93 mmol) of the compound from Example 35A in 20 ml of tetrahydrofuran was added, and the mixture was stirred for 1 h. 1.01 g (7.11 mmol) of methyl iodide were added at −78° C., and the reaction mixture was warmed to RT. It was then diluted with dichloromethane, the phases were separated, and the organic phase was washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.45 g (80% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:17]=1.[H][H]>CO.[C].[Pd]>[NH2:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:17]=1)[N:2]([CH3:1])[C:11]2=[O:12]
Reactant: [H][H]
Reactant: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2ccc(N)cc2c1=O
Yield: 44 %

Procedure:
3-Methyl-6-nitro-2-[3-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone (105 mg, 0.248 mmol) was dissolved in methanol (3 mL), and 10% palladium-carbon (26.4 mg, 0.0248 mmol) was added thereto and stirred in a hydrogen atmosphere at room temperature for 4 days. The reaction solution was filtered through Celite, the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel column chromatography (chloroform/methanol=3/1) to obtain the intended compound (42.8 mg, 44%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][N:26]=[C:25]([CH3:28])[N:24]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].I[CH3:35]>O1CCCC1>[CH3:2][C:1]([O:5][C:6](=[O:29])[N:7]([CH3:35])[CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][N:26]=[C:25]([CH3:28])[N:24]=1)=[O:16])([CH3:4])[CH3:3]
Reactant: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CN(C)C(=O)OC(C)(C)C)n1
Reaction time: 16 h

Procedure:
((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamic acid tert butyl ester (0.4 g) in tetrahydrofuran (5 ml) was treated with sodium hydride (0.1 g). After evolution of hydrogen had ceased iodomethane (0.1 ml) was added and the reaction stirred for 16 hours. The reaction was quenched with ice/water, extracted with diethyl ether (×3), the combined organic extracts dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, diethyl ether) to give the title compound (0.2 g).
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)CCCC2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(O[C:28]2[C:29]3[CH2:39][CH2:38][CH2:37][C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[C:30]=3[N:31]=[C:32](N)[N:33]=2)(=O)=O)=CC=1>>[N:1]1([C:28]2[C:29]3[CH2:39][CH2:38][CH2:37][C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:2][CH2:9][NH:8][CH2:7][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Product: c1ccc2c(c1)CCCc1c-2ncnc1N1CCNCC1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting piperazine for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C. The product was purified by chromatography on silica gel eluting with NH4OH:MeOH:CHCl3 (0.8:8:92) to provide the title compound. 1H NMR (CD3OD) δ 2.32-2.49 (m, 4H), 2.63-2.70 (m, 2H), 2.94-3.01 (m, 4H), 3.47-3.54 (m, 4H), 7.30-7.35 (m, 1H), 7.39-7.44 (m, 2H), 7.65-7.71 (m, 1H), 8.58-8.61 (m, 1H). MS (M+H)+ m/z 281.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:13]([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)[CH:3]=3)[N:8]=2)[CH2:14]1
Reactant: Brc1ccc2nc(NC3COc4ccccc43)ccc2c1
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(Nc2ccc3nc(NC4COc5ccccc54)ccc3c2)n1

Procedure:
The title compound, light yellow foam, MS: m/e=369.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(2,3-dihydro-benzofuran-3-yl)-amine (see example 96, step A) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24]O)[O:22][C@@H:21]([N:26]2[C:43]3[N:42]=[CH:41][N:40]=[C:30]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]=3[N:28]=[CH:27]2)[C@@H:20]1[O:44][CH3:45])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S(Cl)(=O)=O)=CC=1)([O-])=O.[Li][N:60]=[N+:61]=[N-:62]>>[N:60]([CH2:24][C@H:23]1[O:22][C@@H:21]([N:26]2[C:43]3[N:42]=[CH:41][N:40]=[C:30]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]=3[N:28]=[CH:27]2)[C@H:20]([O:44][CH3:45])[C@@H:19]1[O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:61]=[N-:62]
Reactant: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Reactant: [Li]N=[N+]=[N-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CN=[N+]=[N-])O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21

Procedure:
The low selectivity in the tosylation of guanosine derivative 6 prompted us to to use 3'-hydroxyl protection in the preparation of adenosine analog. Thus, 5'-O-DMT derivative 12 was converted to 3'-O-TBDPSi derivative which was 5'-deprotected to yield 13 with TFA in CH2Cl2. The reaction of 13 with a more reactive sulfonylating agent, p-nitrobenzenesulfonyl chloride, yielded unexpectedly a 2:1 mixture of 5'-O-p-nitrobenzenesulfonyl and 5'-chloro-5'-deoxy substituted derivatives 14 and 15. The mixture was treated with LiN3 at 80° C. overnight to afford 5'-azido-5'-deoxy derivative 16 in good yield. Catalytic hydrogenation of 16 proceeded smoothly to afford 5'-amino derivative 17 which was, without purification converted to 5'-N-MMTr protected derivative 18. Cleavage of the 3'-O-TBDPSi group was achieved using tetrabutylammonium fluoride and the resulting 19 was phosphitylated under standard conditions to give the 3'-O-phosphoramidite 20 in 74% yield (FIG. 8C).