Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[NH2:13][CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[NH:19][CH:18]1[CH:23]([CH3:25])[CH3:24])=[O:16]>>[CH:23]([CH:18]1[NH:19][C:20](=[O:22])[CH2:21][N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])([CH3:25])[CH3:24]
Reactant: CC(C)C1NC(=O)CN1C(=O)CN
Reactant: CCOC(=O)CN1CCCC1=O
Product: CC(C)C1NC(=O)CN1C(=O)CNC(=O)CN1CCCC1=O
Temperature: 110 °C
Yield: 38.8 %

Procedure:
A mixture of ethyl 2-oxo-1-pyrrolidineacetate (7 g) and 1-(2-aminoacetyl)-2-isopropyl-4-imidazolidinone (4 g) was heated at 110° C. for 8 hours. After cooling the oily residue was chromatographed on a silica gel column (eluant dichloromethane/methanol 9:1). The selected fractions were collected, evaporated under vacuum and the residue was triturated with diisopropyl ether to yield 2.6 g of the title compound, m.p. 104°-106° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=310 (M.+), 267 (M.+ --C3H7).
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15]C1C2OCCNC=2C=CC=1.CCC([O-])=O>>[CH3:15][C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CNc2cccc(F)c2O1
Reactant: Cc1cccc2c1OCCN2
Agent: CCC(=O)[O-]
Product: Cc1cccc2c1OC(C(N)=O)CN2

Procedure:
This compound is obtained using the same experimental conditions as those used for the synthesis of intermediate (4b) but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-ethyl carboxylate (5b) with 3,4-dihydro-8-methyl-2H-1,4-benzoxazine-2-ethyl carboxylate (5c), [220120-58-1]. The title compound of formula (4c) is obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13](O)[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=1)[CH3:6].O>C(Cl)(Cl)Cl>[Br:2][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:5][CH3:6])=[CH:12][N:11]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Yield: 89.8 %

Procedure:
2.93 g (0.01 mol) PBr3 was added to a solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in 50 mL chloroform at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water furnished 3 g (50%) of desired product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]1=[O:17])[CH:2]=[CH2:3].Cl>CCOC(C)=O>[CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCN1CCNCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a stirred solution of 1-(2-propenyl)-4-tert-butyloxycarbonyl-2-piperazinone (11 g, 46 mmol) in EtOAc (100 mL) at 0° C. was bubbled HCl gas for 10 min. The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 1 h. The solvent was removed in vacuo to yield the hydrochloride salt of the title compound as a white solid. ES MS (M+H)=141.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C2)nc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
Ethyl 2-[(3S)-3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}pyrrolidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (237b) (215 mg, 0.52 mmol) was dissolved in methanol (5 mL). A 2 N aqueous lithium hydroxide solution (2.61 mL, 5.22 mmol) was added, and the mixture was stirred at 40° C. for two hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (5 mL) was added to the aqueous layer. The precipitated solid was collected by filtration and washed with water and ethyl acetate to obtain 155 mg of the title compound as a white solid (77%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[CH2:13][CH2:14][NH:15][CH2:16][C@H:6]3[CH2:5][C:4]=2[CH:3]=1.[CH2:17](B(O)O)[CH2:18][CH3:19].[F-].[K+]>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:19]([N:15]1[CH2:14][CH2:13][N:7]2[C:8](=[O:12])[C:9]3[CH:10]=[CH:11][C:2]([CH2:5][CH2:6][CH3:16])=[CH:3][C:4]=3[CH2:5][C@@H:6]2[CH2:16]1)[C:18]1[CH:17]=[CH:4][CH:3]=[CH:2][CH:11]=1
Reactant: CCCB(O)O
Reactant: O=C1c2ccc(Cl)cc2C[C@@H]2CNCCN12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1COCCO1
Product: CCCc1ccc2c(c1)C[C@@H]1CN(Cc3ccccc3)CCN1C2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of (R)-9-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (50 mg, 0.15 mmol), bis(tri-t-butyl phosphine) palladium (2.3 mg, 0.0045 mmol), propyl boronic acid (16 mg, 0.18 mmol), and potassium fluoride(19 mg, 0.33 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed, heated to 100° C. and stirred for 6 h under nitrogen atomsphare. Then the mixture was cooled down to room temperature, diluted with 10 ml of EtOAc and filtered through celite pad. The filtrate was concentrated to give the desired product which was used for next step without further purification. MS (ESI) 335 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].O>C(#N)C>[C:41]([O:45][C:46](=[O:49])[CH2:47][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4-hydroxybenzyl)-3-tritylthiazolidin-2,4-dione (20.0 g) in acetonitrile (200 ml) was added cesium carbonate (21.0 g), followed by bromoacetic acid t-butyl ester (7.4 ml) and the mixture was stirred at 25° C. for 3 hours. To the reaction mixture was added water and the organic layer was separated and concentrated in vacuo. The residue was extracted with toluene and the extract was washed with diluted hydrochloric acid and water and concentrated in vacuo to give the desired compound (24.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])=[CH:35][CH:34]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3ccc(C(=O)O)cc3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 54.4 %

Procedure:
Starting with 0.157 g (0.76 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.391 g (0.75 mmol) of 2-[(5-bromopentyl)oxy]-5-[[4-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.240 g; 63.6% overall yield) was obtained as a white solid, mp 175°-177° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].CCOCC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:7][C:4]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[C:2]([NH:1][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[O:6][N:5]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1noc(N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(5-amino-3-methylisoxazol-4-yl)phenyl]piperazine-1-carboxylate (900 mg, 2.51 mmol) and DMAP (1.02 g, 8.3 mmol) in CH2Cl2 (25 mL) at 0° C. under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) dropwise and the reaction was warned to rt and stirred for 1 hour. Additional aliquots of DMAP (1.02 g, 8.3 mmol) and 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) were added and the reaction mixture was stirred for 2½ hours. Et2O was added and the reaction was poured into aqueous 10% HCl, extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (363 mg, 1.509 mmol) in DMF (6 ml) at 0° C. was added NaH (72.4 mg, 1.81 mmol). After 15 minutes of stirring at 0° C., a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (525 mg, 2.26 mmol) in DMF (1 ml) was slowly added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (373 mg, 1.16 mmol, 77% yield) as a yellow solid. MS [M+H] found 323.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25](F)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[F:37][C:38]1[CH:39]=[C:40]([NH2:46])[CH:41]=[N:42][C:43]=1[O:44][CH3:45]>C1COCC1>[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25]([NH:46][C:40]2[CH:41]=[N:42][C:43]([O:44][CH3:45])=[C:38]([F:37])[CH:39]=2)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: Cc1nc(N)nc(-c2cc(C(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 1.279 mL, 1.279 mmol) was added to an orange-brown solution of 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (201.2 mg, 0.533 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 91 mg, 0.640 mmol) in THF (5.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1.5 h. Additional sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.300 mL, 0.300 mmol) was then added, and the resulting mixture was stirred at 0° C. for 30 min. Excess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL), and the resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) furnished 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.0 mg, 0.482 mmol, 91% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.26 (dd, J=12.3, 2.2 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.04 (d, J=2.3Hz, 1H), 5.40 (br. s., 2H), 4.02 (s, 3H), 3.67 (dd, J=6.2, 2.8 Hz, 2H), 2.91 (q, J=6.5 Hz, 1H), 2.57 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 0.87 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −139.42 (s, 1F). m/z (ESI, +ve) 500.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:10][N:11]([CH:12]([CH2:16][CH3:17])[CH2:13][O:14][CH3:15])[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:15][O:14][CH2:13][CH:12]([N:11]1[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[C:9]([C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)=[CH:10]1)[CH2:16][CH3:17]
Reactant: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(OC)nccc21
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(=O)[nH]ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-(4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzonitrile (38.0 mg) in acetonitrile (3 mL) were added sodium iodide (42.5 mg) and chloro(trimethyl)silane (0.144 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (26.2 mg).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1([C@H:14]2[NH:17][C:16](=[O:18])[C@@H:15]2[O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:1]1([C:5]([N:17]2[C@H:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@@H:15]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:16]2=[O:18])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)C2CCC2)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using cyclobutylcarbonyl chloride, (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one was converted to the title product: 1H NMR (CDCl3) δ 0.18-0.61 (m, 15H), 1.66-2.22 (m, 6H), 3.61 (m, 1H), 4.89 (d, 1H, J=5.7 Hz), 4.94 (d, 1H, J=5.7 Hz), 7.03-7.18 (m, 5H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][N:8]=1)(=O)=O.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O-])=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].[K+].[Cl-].[NH4+]>CS(C)=O>[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][N:8]=2)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27]
Reactant: NS(=O)(=O)c1ccc([O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COS(C)(=O)=O)nc2)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(N)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 55 %

Procedure:
To a solution of tert-butyl 4-[2-(methanesulfonyloxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1(3)) (24 mg, 0.065 mmol) in dimethyl sulfoxide (1 mL) was added potassium 4-sulfamoylphenolate (14 mg, 0.065 mmol). The mixture was stirred at room temperature for 3.5 hours, to which was added saturated aqueous ammonium chloride solution and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/8 and chloroform/methanol=200/1→20/1) to give the title compound as a white crystal (16 mg, yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)=[O:4].[NH2:15][CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1>>[O:14]=[C:12]([NH:15][CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1)[CH2:11][N:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCN(CC(=O)O)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Product: COC(=O)C1CCN(CC(=O)NCc2nc3c(c(=O)[nH]2)COCC3)CC1
Yield: 39.7 %

Procedure:
The title compound (1.2 g) was prepared according the general procedure of Example 1 from 2-(4-(methoxycarbonyl)piperidin-1-yl)acetic acid (2.2 g, 11 mmol) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.5 g, 8.3 mmol). MS m/z 365.3 (M+1), retention time=1.46 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH3:35])[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOC(=O)c1cn(C)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (7.63 g), ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (3.0 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.78 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carboxylate as pale-brown crystals (8.03 g, yield 98%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]([CH3:48])[C@@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][C@@H:43]([N:42]([CH3:48])[CH3:41])[CH2:44]3)=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN(C)[C@@H]1CCNC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CC[C@@H](N(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and (R)-3-dimethylamino-pyrrolidine are used as reactants.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]=2[CH2:2][NH:1][S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[CH:15][CH:14]=1)=[O:26]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Yield: 74.7 %

Procedure:
The product of step H (30 mg, 0.065 mmol) was diluted with methylene chloride (1 mL) followed by the addition of 4-fluorobenzene-1-sulfonyl chloride (15 mg, 0.078 mmol) and DIEA (0.024 mL, 0.14 mmol). After stirring the reaction for 4 hours, the reaction mixture was placed directly onto a preparative tlc plate 0.5 mm and eluted with hexanes:ethyl acetate (3:1) to yield 30 mg of methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fluorophenyl-sulfonamido)methyl)phenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH:7]=[C:8]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2cccc(C)c2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(C)c2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
ethyl 7-methyl-1H-indole-2-carboxylate (500 mg, 2.46 mmol) was dissolved in DMF (20 mL) and granular potassium carbonate (425 mg, 3.08 mmol) and p-chlorobenzylchloride (0.39 mL, 3.08 mmol) were added The mixture was stirred for 3 d at 60° C., after which time the incomplete reaction was terminated by dilution with ethyl acetate and subsequent washing with brine (3×). The organic phase was dried over magnesium sulfate, concentrated, and purified vial silica gel flash chromatography (80 g silica, 40% EtOAc/hexanes.) The title compound was obtained as white crystals. (Yield: 390 mg, 1.19 mmol, 46%) 1H NMR (400 MHz, CDCl3) 7.56, 7.41, 7.32-6.96, 6.78, 6.08, 4.31-4.25, 2.54, 1.34