Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([NH2:36])[CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][C:31]=1[NH:36][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1CCCCC(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Reaction time: 12 h
Yield: 49.9 %

Procedure:
A 25-mL RB-flask was charged with 5-(2-methoxyphenyl)pentanoic acid (53.0 mg, 0.250 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg, 0.200 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL) The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate (48.4 mg, 50.0%): 1H NMR (400 MHz, CDCl3) δ 8.36-8.13 (m, 1H), 7.39 (s, 1H), 7.26-7.06 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.75 (m, 3H), 4.41-4.02 (m, 2H), 3.80 (s, 3H), 2.90-2.70 (m, 2H), 2.70-2.63 (m, 2H), 2.63-2.51 (m, 1H), 2.49-2.32 (m, 2H), 1.87-1.72 (m, 4H), 1.72-1.63 (m, 2H), 1.63-1.52 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:2]1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([Cl:26])([F:25])[F:24])=[N:21][N:22]=2)[N:19]=1>>[Cl:26][C:23]([F:24])([F:25])[C:20]1[N:18]2[N:19]=[C:14]([N:10]3[CH2:9][CH2:8][N:7]([CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:12][CH2:11]3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: c1cc(CN2CCNCC2)cs1
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(Cc4ccsc4)CC3)nn12
Yield: 70 %

Procedure:
A mixture of 1-(thiophen-3-ylmethyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(thiophen-3-ylmethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 70% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12](O)[CH2:11][CH:10]1[CH3:20])=[O:8])[CH3:2].[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([N:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29][CH2:28]2)[CH2:11][CH:10]1[CH3:20])=[O:8])[CH3:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OCC
Product: CCOc1ccc(C(=O)N2c3ccccc3C(N3CCCc4ccccc43)CC2C)cc1OCC
Yield: 33.4 %

Procedure:
Starting with 1-(3,4-diethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (600 mg, 1.70 mmol) prepared in Reference Example 20 and 1,2,3,4-tetrahydroquinoline (679 mg, 5.23 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (267 mg, yield: 34%) as a white crystal. (cis:trans=1:1.4)
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([NH:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:27]([O-])=[O:28])([CH3:23])([CH3:22])[CH3:21].[K+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:20]([NH:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:27]([N:16]1[CH2:15][CH2:14][N:13]([C:11]2[C:12]3[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)NCC(C(=O)[O-])c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C(CNC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (31.7 mg, 0.103 mmol) and potassium 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (30.3 mg, 0.103 mmol) in DMF (1.0 mL) was treated with DIEA (38 uL, 0.217 mmol) and HBTU (43 mg, 114 mmol), respectively, at room temperature. The mixture was allowed to stir for 18 hours to completion, and the solution was partitioned between ethyl acetate and water. The aqueous was extracted twice, and the organics were combined. The organic portion washed with water (3×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (eluted with water:acetonitrile gradients modified with 1% ammonium acetate) to afford the pure 3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (20 mg, 41%) as a white solid. LCMS (APCI+) m/z 472.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-Bromo-3-(6-methoxy-biphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12](=[O:14])[O:11][N:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)=[C:2]([NH:1][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)=[O:25])[CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1-c1noc(=O)[nH]1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cc(Cl)ccc1-c1noc(=O)[nH]1
Reaction time: 16 h
Yield: 62.7 %

Procedure:
3-(2-Amino-4-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one (400 mg, 1.92 mmol) was dissolved in 20 ml dry THF and 3-trifluoromethyl-phenyl-isocyanate (450 mg, 2.40 mmol) was added and the reaction stirred for 16 hours. The solvent was reduced under vacuum and the product recrystallised from ethyl acetate and heptane to yield 480 mg (63%) of off-white crystalline solid (m.p. 246-248; decomposition).
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>ClCCl.O.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of 4-(1-phenoxyethyl)benzoic acid (121 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol) and triethylamine (0.2 mL) in dichloromethane (5 mL) was stirred at 25° C. for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (100 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20](OCC)=[O:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([CH2:20][OH:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(CO)nn1CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of Example 46 (65 mg, 0.17 mmol) in tetrahydrofuran (2.5 ml) was cooled to −78° C. and treated with lithiumaluminium hydride (1M in THF) (170 μL, 0.17 mmol). After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to 0° C. for 1 hour and was then allowed to warm to room temperature. After stirring at this temperature for 18 hours, water (1 ml) was added. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (42 mg) as a colourless oil, which solidified on standing, m.p. 89-90° C.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=O)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[CH:19])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of compound 2a (562 mg, 1.80 mmol) in MeOH (10 mL), solid K2CO3 (0.749 g, 5.41 mmol) was added followed by dimethyl(1-diazo-2-oxopropyl)phosphonate (382 mg, 1.98 mmol) in MeOH (5 mL). The reaction was stirred at rt for 12 h and concentrated. The residue was dissolved in DCM (40 mL) and washed with water (25 mL). The aqueous layer was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with 1:1 EtOAc/heptane, filtered and dried to give compound 80a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C12H11BrN4O: 307.0 (M+H). found: 307.1.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C@@H:11]1[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]1
Reactant: Fc1ccc2[nH]cc([C@@H]3CC[C@H](NCc4ccccc4)C3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1
Yield: 87.9 %

Procedure:
A mixture of cis-benzyl-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.45 g, 1.46 mmol), 0.2 g 10% Pd/C and ammonium formate (1.0 g, 15.9 mmol) in methanol (30 mL) were refluxed under nitrogen for 4 hours. The reaction mixture was cooled, filtered through celite, and concentrated. The residue was diluted with 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 0.28 g (100%) of the title compound as a thick oil: MS (ESI) m/z 219 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](O)[C:20]=2[N:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[N:16]1[C:25]2[C:20](=[C:21]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc2nccnc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccc2nccnc12)C(F)(F)F
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Add trifluoromethanesulfonic anhydride (0.66 mL, 3.94 mmol) to a solution of quinoxalin-5-ol (Yamamoto, T. et al., J. Am. Chem. Soc. 1996, 118, 3930-3936; 500 mg, 3.42 mmol) in pyridine (6.8 mL) at 0° C. Allow the reaction to warm slowly to room temperature over 18 h. Add saturated aqueous sodium bicarbonate solution (100 mL) and extract the mixture with methylene chloride (3×100 mL). Dry the combined organic solutions with sodium sulfate, concentrate in vacuo, and purify by flash column chromatography to provide the subtitled compound (810 mg, 85%) as an off-white solid. MS ESI+ m/e 279 (M+1). 1H NMR (CDCl3): δ 8.85 (m, 2H), 8.18 (m, 1H), 7.84 (m, 1H), 7.63 (m, 1H). TLC (SiO2): Rf0.2 (3:1 hexanes/ethyl acetate).
Reaction SMILES: CO[CH:3]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])[CH:5]=O.Cl.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=1)([CH3:18])[CH3:17].C[O-].[Na+]>CO>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[N:26]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[CH:5][N:25]=2)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(C(=N)N)cc1
Reactant: CC[C@H](C)CCCCC(C=O)=COC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)CCCCc1cnc(-c2ccc(OC(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 23 g of (S)-2-(methoxymethylidene)-7-methylnonanal, 26.2 g of 4-isopropoxybenzamidine hydrochloride and 250 ml of absolute methanol was treated dropwise at 10° C. with 80 ml of a 5% solution of sodium methylate in methanol. The reaction mixture was stirred at room temperature overnight and subsequently made acid (pH 4-5) with concentrated hydrochloric acid, filtered and the filtrate was concentrated. The residue was taken up in 500 ml of dichloromethane, washed several times with water, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with hexanethyl acetate (vol. 19:1) and recrystallization from methanol gave 22.2 g of (S)-2-(4-isopropoxyphenyl)-5-(5-methylheptyl)pyrimidine; m.p. 47.2°-47.7° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][C:22]3(OCCO3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:4].[NH2:29][CH2:30][C@H:31]([OH:44])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:22]([NH:29][CH2:30][C@H:31]([OH:44])[CH2:32][O:33][C:34]3[C:42]4[NH:41][C:40](=[O:43])[NH:39][C:38]=4[CH:37]=[CH:36][CH:35]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:4]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
Reference Example 20, 1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methylamide, was hydrolyzed to the corresponding ketone according to the procedure of Reference Example 5, and then reacted with 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one according to the procedure of Example 1 to give the title compound as a tan solid; mp 36-39° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-2.00 (m, 8H), 2.55 (d, 3H), 2.50-3.40 (m, 6H), 3.70-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.55 (d, 1H), 6.60 (d, 1H), 6.80 (t, 2H), 7.35 (d, 2H), 7.60 (d, 2H), 7.90 (q, 1H), 10.60 (br s, 1H), 10.70 (br s, 1H), MS (ES) m/z: 573.1 (MH+); HRMS Calcd. for C27H37N6O6S (MH+): 573.2490. Found: 573.2495.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([O:13]CC)=[O:12])=[N:2]1.CO.O.[OH-].[Li+]>O>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([OH:13])=[O:12])=[N:2]1
Reactant: CCOC(=O)C1=NOC2(CCCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NOC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
Ethyl 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylate (8.12 g, 38.5 mmol, as prepared in the previous step) was placed in a 200 mL round-bottom flask equipped with a magnetic stir bar, and MeOH (75 mL) and water (25 mL) were added. Lithium hydroxide monohydrate (1.77 g, 42.3 mmol) was added as a solid. The reaction was stirred at RT for 20 h, and the solvents were removed under reduced pressure. The resulting solid was triturated with ether and collected by filtration. The solid was then dissolved in water (200 mL) and acidified to pH 2 with 3 M aq HCl. The precipitate was isolated by filtration, washed well with water, air dried, and dried under vacuum. The filtrate was extracted three times with DCM (50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The initial precipitate and the material from the extraction were combined, giving 5.81 g (83%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 2.93 (s, 2H), 1.72-1.89 (m, 4H), 1.60-1.72 (m, 2H), 1.37-1.54 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+]>O>[C:1]1([C:7]2[O:8][C:9]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 87.9 %

Procedure:
15.0 g of ethyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate, 250 ml of methanol, 20 ml of water and 6.3 g of potassium hydroxide are treated in Example 8. 12.0 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 88%
Reaction SMILES: OC(=CC([O-])=O)C.CS(Cl)(=O)=O.[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41](OS(C)(=O)=O)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1.C(N(CC)CC)C>[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: C1COCCN1
Agent: CC(O)=CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 0.42 h

Procedure:
One suspends p-nitrobenzyl α-[3-benzyl-7-oxo-ethylidene)-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylideneacetate (2.265 g) in anhydrous tetrahydrofuran (30 ml), adds dropwise a solution of triethylamine (1.11 g) and methanesulfonyl chloride (630 mg) in tetrahydrofuran (2 ml) at 1° to 2° C., and stirs for 25 minutes. To the produced solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds a solution of morpholine (480 mg) in tetrahydrofuran (2 ml), and stirs for 15 minutes to give a solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -20° C., adds pyridine (396 mg) and a solution of bromine in carbon tetrachloride (1 mole/liter: 5 ml), pours into diluted hydrochloric acid after 15 minutes, and extracts with ethyl acetate. The extract solution is washed with water, dried over magnesium sulfate, and evaporated. Purification of the obtained residue by chromatography over silica gel (50 g), from the fraction eluted with a mixture of benzene containing 10% ethyl acetate gives p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidene)acetate (2.36 g). Yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CCSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSCC)cccc12
Yield: 93.7 %

Procedure:
2 mg (0.03 mmol) of copper powder were added to 1.38 g (3.00 mmol) of the compound from Example 14A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 1.13 g of the target compound with a purity of 84% (78% of theory) were obtained.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.BrC1C=[C:21]2[C:26](=[N:27][CH:28]=1)NC(=O)CC2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N1CCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[N:27]1([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:26][CH2:21][CH2:28]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), prepared (as in J. Med. Chem. 2003, 46, 9, 1627-1635) from 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one described in U.S. Pat. No. 4,866,074 (Rorer Pharmaceutical Corp.), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), azetidine (16 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified twice on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give the title compound (31 mg, 62%) as a white solid.