Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1CCN(C2C=CN=C(NCC(C)C)N=2)C1.[C:18]([O:22][C:23](=[O:41])[NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32](NCC(C)C)[N:31]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19].[ClH:42]>CO>[C:18]([O:22][C:23](=[O:41])[NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:42])[N:31]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cl
Reactant: CC(C)CNc1nccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)n1
Agent: CC(C)CNc1nccc(N2CC[C@@H](N)C2)n1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a slurry of 2,4-dichloropyrimidine (2.05 g, 13.7 mmol) and N,N-diisopropylethylamine (3.60 mL, 20.6 mmol) in i-PrOH (12 mL) was added (R)-3-N-Boc-amino pyrrolidine (2.69 g. 14.4 mmol). The mixture was heated at 160° C. in a microwave for 2 h. The reaction was cooled to rt and concentrated, and the crude residue was purified by FCC (0 to 50% EtOAc/hexanes) to yield a white solid (2.10 g, 51%). MS (ESI): mass calcd. for C13H19ClN4O2, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=6.0, 1H), 6.19 (d, J=6.0, 1H), 4.85-4.47 (m, 1H), 4.40-4.16 (m, 1H), 3.94-3.08 (m, 4H), 2.46-2.17 (m, 1H), 2.12-1.78 (m, 1H), 1.45 (s, 9H). [(3R)-1-(2-Isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. To a slurry of [(3R)-1-(2-chloro-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (103 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in i-PrOH (1.5 mL) was added isobutylamine (30 mg. 0.41 mmol). The mixture was heated to 140° C. in a microwave for 6 h. The reaction was cooled to room temperature and concentrated. The crude residue was purified by FCC (0 to 10% MeOH/CH2Cl2) to yield the desired product (93 mg, 80%). MS (ESI): mass calcd. for C17H29N5O2, 335.2; m/z found, 336.3 [M+H]+. 1H NMR (CDCl3): 7.83 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.98-4.80 (m, 1H), 4.78-4.61 (m, 1H), 4.38-4.20 (m, 1H), 3.79-3.26 (m, 4H), 3.23-3.11 (m, 2H), 2.32-2.09 (m, 1H), 1.99-1.77 (m, 2H), 1.45 (s, 9H), 0.95 (d, J=6.7, 6H). 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine. To a solution of [(3R)-1-(2-isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (93 mg, 0.28 mmol) in MeOH (0.5 mL) was added HCl (4.0 M in 1,4-dioxane; 1.0 mL). The reaction was stirred at rt for 2 h, concentrated, and the crude residue was purified by FCC (0 to 20% 2 M NH3 in MeOH/CH2Cl2) to yield the desired product (65 mg, 100%). MS (ESI): mass calcd. for C12H21N5, 235.2; m/z found, 236.2 [M+H]+. 1H NMR (CDCl3): 7.82 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.87 (s, 1H), 3.75-3.51 (m, 3H), 3.48-3.38 (m, 1H), 3.20 (dd, J=6.7, 6.1, 3H), 2.16 (d, J=6.3, 1H), 1.87 (dt, J=13.4, 6.7, 1H), 1.81-1.71 (m, 1H), 1.47 (s, 2H), 0.95 (d, J=6.7, 6H). The compounds in Example 24 through Example 30 were prepared using methods analogous to those described for Example 23.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:21]/[S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:23])[F:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: O=Cc1ccccc1I
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(/N=C/c1ccccc1I)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To the mixture of 2-iodobenzaldehyde (11) (12.3 g, 53 mmol) and 4-trifluoromethylbenzenesulfonamide (12) (12.15 g, 54 mmol) in CH2Cl2 (110 mL) and THF (27 mL) was added triethylamine (22.5 mL) and titanium(IV) chloride (3 mL) at 0° C. After stirring at 0° C. for 2 h, the solid was separated via Celite filtration. The filtrate was concentrated under reduced pressure to dryness, triturated with toluene to give 27 g of a yellow solid as the crude product (3) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:15]([Si:19]([CH3:25])([CH3:24])[O:20]CC#C)([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(Cl)Cl.[Zn]>[Si:19]([O:20][CH2:14][C:11]1[N:10]=[CH:9][C:3]2[C:2]([CH:13]=1)=[CH:7][N:6]=[C:5]([Cl:8])[CH:4]=2)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:25])[CH3:24]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Agent: [Zn]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc2cnc(Cl)cc2cn1
Temperature: 70 °C

Procedure:
A mixture of N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (530 mg, 1.9 mmol), tert-butyldimethyl(2-propynyloxy)silane (0.59 mL, 2.9 mmol), NiCl2(DPPP) (52 mg, 0.1 mmol), and zinc (252 mg, 3.9 mmol) in acetonitrile (5 mL) was heated at 70° C. under an atmosphere of nitrogen. The cooled reaction mixture was diluted with methylene chloride (50 mL), filtered over Celite, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as an orange waxy solid (340 mg, 57%), which was used in the next step without further purification.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2=[N:29][N:30]([CH3:34])[C:31](=[O:33])[CH2:32][CH:25]2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2=[N:29][N:30]([CH3:34])[C:31](=[O:33])[CH:32]=[C:25]2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CN1N=C2CCN(C(=O)OC(C)(C)C)CCC2CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1nc2c(cc1=O)CCN(C(=O)OC(C)(C)C)CC2
Yield: 52.4 %

Procedure:
3 g DDQ was added to 2.5 g 2-methyl-3-oxo-2,3,4,4a,5,6,8,9-octahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 25 mL dioxane. The reaction was refluxed for 12 h. Then aqueous potassium carbonate solution was added and the mixture was extracted with chloroform. The organic layer was washed with brine. The crude product was purified by column chromatography on silica gel to yield 1.3 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[O:24][CH3:25])=[C:6]([CH3:27])[C:5]([OH:28])=[CH:4][CH:3]=1.O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH3:27])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:13]=[C:12]([CH3:23])[C:11]=1[O:24][CH3:25]
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1C
Temperature: 60 °C
Yield: 21.7 %

Procedure:
To a solution of N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-5-(3-fluorophenyl)-2-methoxy-3-methyl-benzamide (450 mg, 1.17 mmol, 1.0 eq) in THF (6 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 7.04 mL, 7.04 mmol, 6.0 eq). The reaction mixture was heated at 60° C. for 1 h. After cooling to 0° C., water was added dropwise and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1 to 10:1) to give the title compound as a colorless oil (94 mg, 22%).
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]=3[CH:10]=[N:9][C:8]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NCc2cnc3[nH]ccc3c2N1C1CCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ncc2cnc3[nH]ccc3c2n1C1CCCCC1
Yield: 3.3 %

Procedure:
1-Cyclohexyl-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one (18 mg, 0.066 mmol) in chloroform (2 mL) was stirred with manganese dioxide (100 mg, 1.15 mmol) at 50° C. for 5 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=10/1 (v/v)) to give the title compound as a colorless solid (0.58 mg, yield 3.2%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[C:29]([C:40](Cl)=[O:41])=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:40]([C:29]2[C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37](=[O:39])[C:38]=3[CH:26]=[CH:27][CH:28]=2)=[O:41])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccc2c1-c1ccccc1C2=O
Yield: 16.4 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl ]-L-proline 4-phenylbutylamide (134 mg) with 9-fluorenone-4-carbonyl chloride (131 mg) provided 35 mg(18%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32].N>CO.C(Cl)Cl.C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[NH:32])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(N)ccc21
Agent: I
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 24 h
Yield: 27.8 %

Procedure:
Compound 20 (97 mg, 0.266 mmol) and anhydrous ethanol (10 mL) were charged to a dry argon purged flask fitted with magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (98.7 mg, 0.346 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 46 hours at which time, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 (developed twice) shows incomplete consumption of 20. A condenser was added and the mixture heated to reflux for 5 hours. An additional amount of the thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) was added and stirring continued at 65° C. for an additional 24 hours. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) and ethanol (10 mL) were added and stirring continued for an additional 72 hours at reflux. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 (developed twice) shows incomplete consumption of 20. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (1.0 eq) was added and the mixture heated to reflux for 6 hours then stirred at ambient temperature for 48 hours. The mixture was filtered through a sintered glass funnel to remove insolubles, the filtrate concentrated and the residue purified using dry silica gel column chromatography eluting with 30 mL portions of solvent system (2M NH3 in methanol:CH2Cl2, 5:95) to afford an orange oil 21 (35 mg, 27.8%); 1H NMR (DMSO-d6) δ 8.36 (d, 2H, J=8.6 Hz), 8.18 (s, 1H), 7.86 (d, 2H, J=8.8 Hz), 7.75 (d, 1H, J=3.2 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.14-7.05 (2×m, 2H), 6.85-6.80 (m, 1H), 6.69 (s, 1H), 4.29 (m, 2H), 2.91-2.84 (m, 1H), 2.08 and 2.06 (2×s, 3H), 2.03-1.93 (m, 1H), 1.90-1.78 (m, 1H), 1.72-1.63 (m, 1H), 1.61-1.43 (m, 3H), 1.37-1.20 (m, 2H); ESI-MS (m/z, %): 474 (M+1, 100%).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/[C:25](C)=[O:26])=N\O.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:26][CH3:25])[CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc(CI)c(C)o2)c1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and m-anisaldehyde gave 4-iodomethyl-2-(3-methoxy-phenyl)-5-methyloxazole.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:46](Cl)(=[O:48])[CH3:47]>C1COCC1>[CH2:1]([S:3][C@@H:4]1[N:7]([C:46](=[O:48])[CH3:47])[C:6](=[O:8])[C@H:5]1[CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH3:2]
Reactant: CCS[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a -78° C. THF (10 mL) solution of compound 17 (718 mg, 1.26 mmol) was added 1N THF solution (1.5 mL) of lithium bis(trimethylsilyl)amide (1.5 mmol), followed by stirring the solution for 10 min. Acetyl chloride (0.1 mL, 1.5 mmol) was added, and the resultant solution was warmed to room temperature, followed by an additional hour of stirring. The reaction mixture was concentrated, and the residue was partitioned between pH 7.0 aqueous buffer and ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (1:1/Et2O:hexane) to afford 615 mg (90%) of the title product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:5]=1.[CH:22](OC)=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[CH:22][OH:23])[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(=CO)c1ccccc1Oc1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
12.92 g (0.32 mol) of a 60% sodium hydride dispersion in mineral oil were suspended in 400 mL of tetrahydrofuran. After cooling to 0-5° C., a solution containing 45 g (0.16 mol) of methyl 2-(4-chlorophenoxy)phenylacetate (compound VIIIb), as obtained in Example 6, in 300 mL of tetrahydrofuran, was added dropwise while keeping the temperature below 10° C. After the addition, the reaction mixture was stirred at 0-5° C. for 30 minutes. Then, 36.3 g (0.60 mol) of methyl formate were added dropwise, while keeping the temperature below 10° C. After the addition, the reaction mixture was stirred at room temperature overnight. 50 mL of 2 M aqueous hydrochloric acid were added. Then, 200 mL of ethyl acetate were added and the phases were decanted. The organic phase was extracted and washed with 200 mL of water and 200 mL of saturated sodium chloride. The organic phase was concentrated to dryness under reduced pressure, to obtain 40 g of methyl 2-[2-(4-chlorophenoxy)phenyl]-3-hydroxyacrylate (compound IXb) after chromatographic purification. Yield: 80.7%.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CO>[OH:3][CH2:4][C@@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (643 mg, 2.15 mmol) in MeOH (10 mL) was added p-TSA (37 mg, 0.22 mmol), then the solution was stirred at rt for 12 hr. TEA (2 mL) was added, followed by Boc2O (46 mg, 0.21 mmol). After the addition the reaction solution was stirred for another 30 min. The organic solvent was removed under reduced pressure to give the crude product tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate. It was used in the next step without further purification. MS ESI+ve m/z 260 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3ccccc3n2)c1
Yield: 29 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (125 mg, yield: 29.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:22][C:21]1[NH:20][CH:19]=[C:18]3[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=13)[C:5](=[O:11])[NH:6]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: Cc1cccc2c1C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
4-Methyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][C:23](=O)[CH:22]2[CH:28]([CH3:30])[CH3:29])=[CH:10][CH:9]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CCOCC.O>[C:14]1([C:11]2[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C1C(=O)NCCN1Cc1ccccc1-c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)C1CNCCN1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.0M solution of lithium aluminum hydride in tetrahydrofuran (4.8 mL, 4.8 mmol) was cooled to 0°, then a solution of EXAMPLE 12B (0.45 g, 1.31 mmol) in tetrahydrofuran (9 mL) was added dropwise. The reaction was stirred at room temperature overnight. The next day more lithium aluminum hydride solution was added (4.8 mL, 4.8 mmol) and the reaction stirred at room temperature for another two days. The reaction was then cooled to 0° and water (0.75 mL) was carefully added, followed by 4N NaOH (0.75 mL), and additional water (2.2 mL). Na2SO4 and ether (25 mL) were added, and after stirring for 45 minutes ; the mixture was filtered through Celite® (diatomaceous earth). Concentration of the filtrate gave the title compound.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[CH3:37]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>C(Cl)Cl.CO>[C:2]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:37]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 21a (195 mg, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. The Dess-Martin periodinane (184 mg, 0.433 mmol) was added and then the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2×20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 20 mL vial equipped with a stir bar and then MeOH (5 mL) was added. K2CO3 (163 mg, 1.18 mmol) was added and then dimethyl (1-diazo-2-oxopropyl)phosphonate (113 mg, 0.590 mmol) dissolved in MeOH (2 mL) was added. The reaction was stirred at reflux for 3 h. Additional K2CO3 (163 mg, 1.18 mmol)) and diazophosphonate (113 mg, 0.590 mmol) were added and the reaction was refluxed for 6 h. The reaction was cooled to rt and then the solvent was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL) and then the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.85 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.8, 2.4 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.08 (d, J=5.6 Hz, 1H), 3.95-4.03 (m, 4H), 3.88-3.95 (m, 4H), 3.60-3.68 (m, 4H), 3.50-3.60 (m, 4H), 3.28 (s, 1H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H31N7O3: 490.3 (M+H). Found: 490.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)[CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Solvent: ClCCl
Product: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1

Procedure:
A solution of EXAMPLE 89 (150 mg, 0.59 mmol) and 4-chlorobutanoyl chloride (83 mg, 0.59 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hours, and was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to provide the title compound. MS (DCI/NH3) m/z 360 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.66-1.73 (m, 4H), 2.07-2.15 (m, 2H), 2.40-2.46 (m, 2H), 2.48-2.51 (m, 2H), 2.50-2.56 (m, 2H), 3.63 (t, J=6.44 Hz, 2H), 3.96 (s, 2H), 6.93 (d, J=7.67 Hz, 1H), 7.21-7.26 (m, 1H), 7.36 (s, 1H), 7.38-7.46 (m, 1H).