Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:13]1[CH:12]=[CH:11][NH:10][C:9](=[O:8])[C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
2-Benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (5.79 g, 15.4 mmol) was dissolved in TFA (20 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated and washed with 20% EtOAc/Hexane, and concentrated in vacuo to yield 1.0 g (23%) of 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one as a solid: crude MS (AP) m/z 285.1 [(M+H)+, 100].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([S:33][CH3:34])[CH:32]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([S:28][CH3:29])[CH:21]=2)[CH:17]=1)[C:11](OC)=[O:12].Cl>O1CCCC1>[CH3:34][S:33][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([S:2][CH3:1])[CH:32]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([S:28][CH3:29])[CH:21]=2)[CH:17]=1)[CH2:11][OH:12]
Reactant: COC(=O)c1cc(OCc2cc(SC)cc(SC)c2)cc(OCc2cc(SC)cc(SC)c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CSc1cc(COc2cc(CO)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Reaction time: 5 h

Procedure:
To sodium dihydrobis(2-methoxyethoxy)aluminate (70% in toluene, 22.7 g, 0.078 mol), was added dropwise a solution of methyl 3,5-bis(3,5-dimethylthiobenzyloxy)benzoate (21.0 g) in tetrahydrofuran (180 ml) in a stream of nitrogen at 5–10° C. during 30 minutes. After completion of the addition, the mixture was stirred for 5 hours and then poured into 2 L of diluted hydrochloric acid, followed by extraction with 1 L of chloroform. The extract was evaporated to dryness, and the residue was purified by means of chromatography using chloroform as the developing solvent, giving 3,5-bis(3,5-dimethylthiobenzyloxy)benzyl alcohol. The yield was 17.5 g (85.6%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:25][OH:26].[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37](O)=[CH:36][C:34]=2[CH:35]=1)[CH3:28].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([O:26][CH2:25][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=6)[CH2:14][CH2:13]5)[C:6]=4[C:2]=3[CH3:1])=[CH:36][C:34]=2[CH:35]=1)[CH3:28]
Reactant: CCOCc1cc2cc(O)ccc2o1
Reactant: Cc1c(CO)oc2cccc(OC3CCN(Cc4cccnc4)CC3)c12
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCc1cc2cc(OCc3oc4cccc(OC5CCN(Cc6cccnc6)CC5)c4c3C)ccc2o1
Temperature: -30 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a cooled (−30° C.) solution of [3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-benzofuran-2-yl]-methanol (30 mg), 2-ethoxymethyl-benzofuran-5-ol (16 mg) and 1,1′-azobis(N,N-dimethylformamide) (37 mg) in THF (1 ml) was added tributylphosphine (53 μl) and the resulting solution was stirred overnight at −30° C. The resulting suspension was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=20:1 as a developing solvent) to give 3-[4-[2-(2-ethoxymethyl-benzofuran-5-yloxymethyl)-3-methyl-benzofuran-4-yloxy]-piperidin-1-ylmethyl]-pyridine (27 mg) as a colorless oil. FAB-MS: m/z 527 (MH+); 1H-NMR (CDCl3): δ 1.26 (3H, t, J=7 Hz), 1.99 (4H, m), 2.41 (3H, s), 2.42 (2H, m), 2.70 (2H, m), 3.55 (2H, s), 3.61(2H, q, J=7 Hz), 4.52 (1H, m), 4.58 (2H, s), 5.10 (2H, s), 6.60 (1H, d, J=8 Hz), 6.63 (1H, s), 6.97 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.03 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.15 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J1=8 Hz, J2=5 Hz), 7.37 (1H, d, J=9 Hz), 7.68 (1H, dt, J1=8 Hz, J2=2 Hz),8.51 (1H, dd, J1=5 Hz, J2=2 Hz), 8.56 (1H, d, J=2 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:27]([CH3:29])[CH3:28])[C:16]2=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) in DMF (10 ml) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15%-20% AcOEt in hexane) to give the title compound (218 mg) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([CH2:40][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:38][CH:37]=1)[CH3:35]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(C)c23)cc1

Procedure:
The above 4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole and 4-ethylbenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound, 3-(4-ethylphenylmethyl)-4-methyl-1-(β-D-glucopyranosyl)-indole as a colorless powder. APCI-Mass m/Z 412 (M+H). 1H-NMR (DMSO-d6) δ 1.15 (t, J=−1.6 Hz, 3H), 2.41 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.23 (td, J=8.9, 5.2 Hz, 1H), 3.37-3.47 (m, 3H), 3.64-3.69 (m, 2H), 4.16 (s, 2H), 4.51 (t, J=5.3 Hz, 1H), 5.06 (d, J=5.1 Hz, 1H), 5.13-5.15 (m, 2H), 5.34 (d, J=9.0 Hz, 1H), 6.70 (d, J=7.1 Hz, 1H), 6.97 (t, J=7.7 Hz, 1H), 7.07-7.12 (m, 5H), 7.34 (d, J=8.3 Hz, 1H).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:11]=1)[CH3:6])(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([N:10]2[N:9]=[N:8][C:7]([C@H:5]([OH:4])[CH3:6])=[N:11]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1nnn(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)c1nnn(-c2cccc(Cl)c2)n1
Reaction time: 20 h
Yield: 551.7 %

Procedure:
1.25 g (4.68 mmol) (1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl acetate and 0.48 g (11.4 mmol) lithium hydroxide monohydrate were mixed with 3:1 THF/Water (28 mL) and stirred for 20 h. After acidification with aq. HCl, followed by reducing the volume of the mixture in vacuo, followed by dilution with brine and extraction with DCM. 5.8 g (97%) of the title compound was obtained after evaporation & coevaporation with toluene, followed by drying. 1H NMR: 8.15 (m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14 (s, 3H), 1.77 (d, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:35]#[C:36]Br>O.O1CCOCC1>[C:36]([NH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:35]
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CNC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of [S--(R*,R*)] and [R--(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-[4-(trifluoromethyl)phenyl]urea (0.3 g, 0.75 mmol) in water (5 mL) and 1,4-dioxane (5 mL) is added solid sodium bicarbonate (0.06 g, 0.75 mmol) followed by cyanogen bromide (0.1 g, 0.75 mmol). The resulting mixture is stirred 1.5 hour at room temperature before diluting with water and filtering. The solid product is washed with water (2×) and t-butyl-methyl ether (2×). Dry in vacuo at 43° C. for 2 hours, mp 153° C. -154° C. IR (KBr) 3350, 2225, 1674, 1554, 1326, 1115, 699 cm-1 ; NMR (DMSO-d6), 4.61 (m, 1H), 5.04 (m, 1H), 7.19 (m, 10H), 7.57 (m, 6H), 9.04 (s, 1H). Analysis calculated for C23H19F3N4O.0.31H2O: C, 64.24; H, 4.60; N, 13.03. Found: C, 64.24; H, 4.60; N, 12.67.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C(OCC)(=O)C>CO.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 97.6 %

Procedure:
A solution of 4.05 g (17.9 mmol) of 4-azido-1-t-butoxycarbonylpiperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h when the reaction was complete by TLC (10% ethyl acetate in hexanes). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1)[CH3:11].CCN(C(C)C)C(C)C>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH2:10][CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: CC[C@@H]1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (240 mg, 1.46 mmol) in CH3CN (8 mL) were added (3R)-3-ethylmorpholine (244 mg, 1.61 mmol) and Hunig's base (1.02 mL, 5.85 mmol), and the reaction mixture was heated in a microwave at 150° C. for a total of 3 hours, checking the progression of the reaction at regular intervals. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (307 mg). LC-MS (ES) m/z=243, 245 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH2:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Product: CNC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and methylamine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([C:24]3[O:28][C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH2:30]4)=[N:26][C:25]=3[C:36]([F:39])([F:38])[F:37])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:11].N1C2C(=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)C=C1.[N+:68](C1C=CC=CC=1N=C=O)([O-:70])=[O:69]>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:27]2[O:28][C:24]([C:22]([NH:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N+:68]([O-:70])=[O:69])=[O:11])[CH:13]=[CH:14]4)=[O:23])=[C:25]([C:36]([F:39])([F:38])[F:37])[N:26]=2)[CH2:30]1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4c(Cl)cccc4Cl)c3)o2)C1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4ccccc4[N+](=O)[O-])c3)o2)C1

Procedure:
Compound 47 was prepared by the general procedure for compound 45, using compound 44 and 2-nitrophenyl isocyanate as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.55 (br s, 1H), 10.18 (br s, 1H), 8.14 (br d, 1H, J=8.5 Hz), 8.08 (br s, 1H), 8.05 (br d, 1H, J=8.5 Hz), 8.00 (br d, 1H, J=8.0 Hz), 7.79 (tm, 1H, J=7.6 Hz), 7.72 (br d, 1H, J=8.2 Hz), 7.51 (br d, 1H, J=8.2 Hz), 7.46 (m, 1H), 6.84 (m, 1H), 4.13 (m, 2H), 3.06 (br t, 1H, J=12.0 Hz), 2.76 (br t, 1H, J=11.7 Hz), 1.74 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 557.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)=[CH:31][CH:30]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(-c3ccc(CO)cc3)ncc21)NCC1CCOCC1
Temperature: 120 °C
Yield: 32 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 4-(hydroxymethyl)phenylboronic acid (29.8 mg, 0.196 mmol), tetrakis(triphenylphosphine)palladium(0) (15.13 mg, 0.013 mmol), and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and water (0.25 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica-NH, gradient 0-10% MeOH/CHCl3) to afford a white solid, which was recrystallized from EtOH/EtOAc to give the title compound as an off-white solid (19.0 mg, 32.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.21 (m, 2H), 1.48-1.71 (m, 3H), 2.91-3.02 (m, 3H), 3.12-3.32 (m, 5H), 3.50-3.67 (m, 2H), 3.73-4.08 (m, 6H), 4.49-4.61 (m, 3H), 5.19 (t, J=5.68 Hz, 1H), 7.34 (d, J=8.59 Hz, 2H), 7.47-7.51 (m, 1H), 8.08 (t, J=5.94 Hz, 1H), 8.16 (d, J=8.34 Hz, 2H); ESI-MS m/z [M+H]+ calc'd for C24H31N5O4, 454.24. found 454.4.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:22]=[CH:23][CH:24]=1.Cl>>[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][NH:28][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCCCc1cccc(F)c1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4cccc(F)c4)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(3-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(3-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (1.4 g, 37%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.79 (s, 2H), 7.38-7.33 (m, 1H), 7.17 (s, 1H), 7.12-7.08 (m, 2H), 7.06-6.97 (m, 3H), 3.10-3.03 (m, 1H), 2.97-2.89 (m, 2H), 2.71 (dd, J=8, 8 Hz, 2H), 2.57-2.50 (m, 1H), 2.18-2.11 (m, 2H), 1.98-1.92 (m, 2H), 1.89-1.85 (m, 2H), 1.57-1.46 (m, 4H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH2:44])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH:44][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: CCC(=O)c1ccc(NCCN)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C(C)C)CC4)nn23)nc1N
Temperature: 120 °C

Procedure:
30 mg (0.07 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 21 mg (0.09 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}propan-1-one hydrochloride (Example 25A) and 75 μl (0.4 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 120° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (50% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C)=O)=[CH:4][CH:3]=1.[I:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C:25]([CH2:30][C:31](O)=[O:32])=[N:26][S:27](=[O:29])(=[O:28])[C:22]=2[CH:21]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]([OH:15])=[C:30]([C:25]3[NH:24][C:23]4[CH:34]=[CH:35][C:20]([I:19])=[CH:21][C:22]=4[S:27](=[O:28])(=[O:29])[N:26]=3)[C:31]2=[O:32])=[CH:17][CH:18]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-(4-fluoro-benzylamino)-cyclopentanecarboxylate (2.50 g, 10 mmol) in anhydrous N,N-dimethylformamide (25 mL) under a nitrogen atmosphere, (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 3.66 g, 10 mmol), N-methylmorpholine (2.20 mL, 20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) were added sequentially. After stirring at 25° C. for 16 h, the reaction mixture was diluted with ethyl acetate, washed with a 1.0 M aqueous hydrochloric acid solution and saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude amide intermediate.
Reaction SMILES: C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30].[C:31](=[O:33])=[O:32].[Cl-].[NH4+].Cl>O1CCCC1.O>[Br:22][C:23]1[C:24]([F:30])=[C:25]([C:26]([F:29])=[CH:27][CH:28]=1)[C:31]([OH:33])=[O:32]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(F)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 1.6N solution of n-butyllithium in hexane (9.4 ml, 15.0 mmol) and tetrahydrofuran (20 ml) were successively added 2,2,6,6-tetramethylpiperidine (2.50 ml, 15.0 mmol) and 1-bromo-2,4-difluorobenzene (2.90 g, 15.0 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 hr. The pulverized dry ice (5 g) was added, and the mixture was stirred at −78° C. for 2 hr. Saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Water (10 ml) and 1N hydrochloric acid (30 ml) were added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Hexane was added to the residue, and desired product (2.30 g, 64.6%) was collected by filtration as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Cl:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[Cl:7][C:6]1[CH:5]=[N:4][N:3]2[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1n[nH]cc1Cl
Solvent: CC(=O)O
Product: Clc1cnn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 3-amino-4-chloropyrazole is heated at reflux temperature for 6 hours with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in glacial acetic acid to give the product of the example, m.p. 225°-226° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1F)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC([C@H](N)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1F)C(F)(F)F
Reaction time: 8 h

Procedure:
12.29 g (23.3 mmol) of tert-butyl 3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]propanoate (Example 33A, racemic diastereomer mixture) were dissolved in a mixture of 80 ml of ethanol and 20 ml of THF. The solution was inertized with argon, and 745 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with ethanol/THF, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→4:1) and the diastereomers were separated: