Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 μL, 0.22 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (83 mg, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100% water to 100% acetonitrile to give 85 mg of the title product, a compound of the present invention as an oil. 1H NMR (CDCl3) δ 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7-3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, 1H), 6.3 (s, 1H) 7.20-7.45 (m, 5H), 7.8 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]1[N:16]([CH3:41])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[N:20]=[C:19]([N:30]1[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]1[CH2:39][CH3:40])[N:18]=2>CN(C=O)C>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([CH2:14][N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]4=[O:10])[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CC(C)N1CCNC(=O)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)CC3=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.1 %

Procedure:
To a solution 4-isopropylpiperazin-2-one (56 mg, 0.35 mmol) in DMF (3 mL) at 0° C. was added sodium hydride (18 mg, 0.45 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 30 min before the addition of a solution of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (200 mg, 0.44 mmol) in DMF (2 mL). The resulting mixture was stirred at r.t. for 72 h, then partitioned between DCM and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient acetonitrile 30-70%) affording 711 as a white solid (22 mg, 15%). LCMS: RT 2.43 min, [M+H]+ 518.2. 1H NMR (DMSO, 400 MHz): δ 8.01-8.01 (1 H, m), 7.63-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.83 (2 H, s), 4.26 (4 H, brd s), 3.77 (4 H, t, J=4.61 Hz), 3.74 (3 H, s), 3.31 (2 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.15 (2 H, s), 2.69-2.68 (3 H, m), 1.33 (3 H, t, J=7.44 Hz), 0.98 (6 H, d, J=6.50 Hz)
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCN(CC(=NO)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl N-allyl-N-phenacyl-carbamate (3.2 g, 11.6 mmol), hydroxylamine hydrochloride (1.2 g, 17.4 mmol) and sodium acetate (1.4 g, 17.4 mmol) in ethanol (46 mL) is stirred at 70° C. for 18 hours. The reaction is cooled, diluted with water and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of E and Z isomers which is used without further purification (3.16 g, 94%). ES/MS (m/e): 191 (M+H-100).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=[O:4].[Cl:13][C:14]1[N:19]=[N:18][C:17](/[N:20]=[C:21](/N(C)C)\[CH3:22])=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([C:2]2[N:18]3[N:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]3=[N:20][C:21]=2[CH3:22])=[O:4])=[C:6]([F:12])[CH:7]=1
Reactant: C/C(=N\c1ccc(Cl)nn1)N(C)C
Reactant: O=C(CCl)c1ccc(Cl)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F

Procedure:
Combine 2-chloro-1-(4-chloro-2-fluorophenyl)ethanone (1.5 kg, 5.44 mol), and (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylacetimidamide (1.19 kg, 5.72 mol) in DMF (10.14 L) and heat at 120° C. for 5 h. After cooling, add water (30 L) and stir to crystallize the product. Collect the product by filtration and rinse the cake with water (2×12 L) and heptanes (2×10 L) then dry under vacuum to obtain title compound. (1.490 kg, 84.44%; mp=160° C., M+=324).
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:19]([N:32]=1)=[N:20][C:21]1[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:35][C:36]([OH:38])=[O:37]>CN(C)C=O>[O:3]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:16]([CH2:35][C:36]([OH:38])=[O:37])[C:17](=[O:33])[C:18]2[C:19]([N:32]=1)=[N:20][C:21]1[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2cc3c(=O)[nH]c(C(=O)NCCOc4ccccc4)nc3nc2cc1OC
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2cc3c(=O)n(CC(=O)O)c(C(=O)NCCOc4ccccc4)nc3nc2cc1OC
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (0.22 g., 4.6 mM of 50%); N-(2-phenoxyethyl) 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxamide (1.0 g., 2.2 mM); bromoacetic acid (0.319 g., 2.3 mM) and N,N-dimethylformamide (50 ml.) is refluxed for 6 hours and then cooled to room temperature. The precipitate which forms is separated by filtration and dried under vacuum to give 0.476 g. (43%) of product; m.p. 310°-315° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:6][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:22]=12)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: Fc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 60 °C

Procedure:
(S)-(−)-3-methylamino-1-(2-thienyl)-propan-1-ol (20.0 g) and 1-fluoronaphthalene (68.3 g) were charged into a 4-neck round bottomed flask. Potassium tert-butoxide (13.1 g) and DMSO (36.0 g) were then added, and the resulting mixture was heated to 60° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled down and washed with water. Layers were separated, and the organic layer was further extracted with 32% HCl(aq) (14.7 g) to separate Duloxetine® from 1-floronaphthalene. The acidic aqueous layer was adjusted to pH 12-13 with 45% NaOH(aq) (17.6 g) to obtain Duloxetine® in a free base form as an oily liquid (31.3 g, 90%). Optical purity of the resulting Duloxetine® measured by chiral HPLC was 95% e.e.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([N:29]2[CH2:35][CH:34]3[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:28])[C:13]1=[O:38])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C.C(OCC)(=O)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([N:29]2[CH2:35][CH:34]3[CH2:33][CH2:32][CH:31]([CH2:37][CH2:36]3)[CH2:30]2)=[O:28])[C:13]1=[O:38]
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.23 g), 10% palladium on carbon (50% wet, 250 mg) and ammonium formate (600 mg) in ethanol (15 ml) was stirred at room temperature for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo to afford a residue, which was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine successively. After drying over sodium sulfate, the solvent was evaporated in vacuo to afford a residue, which was triturated in diisopropyl ether and collected by filtration to give (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (792 mg, 87.0% yield) as a crystalline powder.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[H][H].[Cl-].[Na+]>[Ni].C(O)C.O>[N:1]1([CH2:10][CH2:11][CH2:12][NH2:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: [H][H]
Reactant: N#CCCn1cnc2ccccc21
Agent: [Ni]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCCCn1cnc2ccccc21
Reaction time: 20 h

Procedure:
4.2 Grams of 1H-benzimidazole-1-propionitrile, 0.2 grams sodium hydroxide, 1 gram of Raney nickel catalyst in about 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for about 20 hours. The hydrogen uptake had stopped by this time with a total uptake of about 1300 ml. The reaction mixture was filtered and the catalyst was washed first with ethanol and then with water. The filtrates were combined and the solvent evaporated to leave a yellowish oil. The oil was dissolved in water, the water was saturated with sodium chloride, and the mixture was extracted with three portions of methylene chloride. The methylene chloride extracts were combined, washed with sodium chloride solution and then dried over potassium carbonate. The mixture was then filtered and the solvent evaporated to leave a yellowish oil which was then distilled to give 1H-benzimidazole-1-propanamine boiling at 167°-170° C. at 1-1.3 mm pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:4][CH3:5].[Br:13][CH2:14][CH2:15]Br>O1CCCC1>[Br:13][CH2:14][CH2:15][N:7]([O:6][CH2:3][CH2:4][CH3:5])[C:8](=[O:12])[O:9][CH2:10][CH3:11]
Reactant: CCCONC(=O)OCC
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCON(CCBr)C(=O)OCC
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
8.73 g (218 mmol) of 60% sodium hydride was suspended in 200 ml of dry tetrahydrofuran, and 50 ml of a dry tetrahydrofuran solution containing 26.7 g (182 mmol) of ethyl N-n-propoxycarbamate, was dropwise added thereto under cooling with ice at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was stirred at the same temperature for 20 minutes and again cooled with ice. Then, 121.4 g (646 mmol) of 1,2-dibromoethane was added all at once. The temperature was gradually raised and then the mixture was refluxed under heating for 2 hours. The mixture was left to cool to room temperature, and the solvent was partially distilled off under reduced pressure. The residue was poured into 100 ml of ice water and extracted three times with 100 ml of chloroform. The chloroform layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then 42.0 g of ethyl N-(2-bromoethyl)-N-n-propoxycarbamate was obtained by distillation under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12](N1C=CN=C1)=[O:13]>O1CCCC1.CCOCC>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:12]([O:11][CH3:10])=[O:13])[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: COC(=O)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
46.3 g (0.32 mol) of 6-chloro-2,4-diamino-pyrimidine are dissolved in 1000 ml of tetrahydrofuran and treated with 57.9 g (0.517 mol) of potassium tert.butylate. The gel-like precipitate is stirred at room temperature for 1 hour. A solution of 60.5 g (0.48 mol) of 1-methoxycarbonylimidazole in 100 ml of ether is added thereto at a temperature of 10° within 90 minutes. The mixture is thereafter stirred at 25° for a further 2 hours, the solvent is then evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The organic solution is washed with cold water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue is crystallized from acetone/ether. After recrystallization from chloroform/methanol/hexane, there is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate of melting point 225°-226°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.Br[C:34]1[CH:35]=[N:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[F:29][C:28]([F:30])([F:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:18]1[CH2:17][CH2:16][N:15]([C:12]2[N:13]=[CH:14][C:9]([C:34]3[CH:35]=[N:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)=[CH:10][N:11]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)OC1(C)C
Reactant: CCOC(=O)Cn1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)cn1
Temperature: 120 °C

Procedure:
Into a 50-mL round-bottom flask equipped with a magnetic stirbar and reflux condenser was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidine (311 mg, 1.35 mmol), ethyl (4-bromo-1H-pyrazol-1-yl)acetate (400 mg, 0.89 mmol), PdCl2(dppf) (36 mg, 0.05 mmol), 2 M aqueous sodium carbonate solution (0.89 mL, 1.8 mmol) and DMF (4 mL). The resulting suspension was degassed under nitrogen for 20 min and then heated in the microwave to 120° C. for 20 min. The mixture was poured into a 125-mL separatory funnel containing a saturated aqueous KH2PO4 solution (50 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography through silica gel, eluting with 30% EtOAc in hexanes to 70% EtOAc in hexanes as a gradient gave the title compound as a white solid. MS (ESI, Q+) m/z 476 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](O)=O)=[C:17]([CH3:26])[C:16]=1[CH3:27]>>[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18](/[CH:19]=[CH:20]/[C:21]2[NH:1][C:2]3[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=3[N:8]=2)=[C:17]([CH3:26])[C:16]=1[CH3:27]
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(C)c1C
Yield: 21.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.74 g (10.2 mmol) of 5,6-diamino-1,3-dimethyluracil and 2.42 g (11.8 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile to give 750 mg (yield 22%) of Compound 84 as a white powder.
Reaction SMILES: [Li][CH3:2].[Li+].[Br-].C[Si](Cl)(C)C.[CH2:10]([O:12][C:13](=[O:30])/[CH:14]=[CH:15]/[C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:11].[Cl-].[NH4+].[OH-].[NH4+]>C1COCC1.[Cu]I>[CH2:10]([O:12][C:13](=[O:30])[CH2:14][C@H:15]([C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:2])[CH3:11]
Reactant: CCOC(=O)/C=C/[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [Li]C
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To CuI (3.36 g, 17.64 mmol) in THF (15 mL) was added at −78° C. MeLi.LiBr (1.5M in ether, 23.5 mL, 35.28 mmol), and the resulting mixture was stirred at −78° C. for 15 min. TMSCl (1.52 mL, 17.64 mmol) and Me2CuLi (generated above) were added in sequence at −78° C. to (S,E)-tert-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (0.88 g, 2.94 mmol), and the resulting mixture was slowly warmed up to rt. Ammonium chloride-ammonium hydroxide buffer (pH˜8) was added to the reaction mixture. The mixture was extracted with ether, washed with brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 2:8=ethyl acetate:hexanes) gave (S)-tert-butyl 4-((R)-4-ethoxy-4-oxobutan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:35])=[O:34]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:13][N:12]([C:20]([N:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:34])=[O:35])[CH2:44][CH2:43]4)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)N2CCN(CCCS(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 9, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (53 mg, 0.11 mmol) was reacted with 1-(3-methanesulfonyl-propyl)-piperazine (34 mg, 0.14 mmol) and triethylamine to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1′-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 61 mg, 79%).
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]2[N:9]([CH3:13])[C:10](=[O:12])[O:11][C:7]=2[CH:6]=[C:5]([N:14]2[CH2:18][C@H:17]([C:19](OC)=[O:20])[O:16][C:15]2=[O:23])[CH:4]=1>CO>[F:2][C:3]1[C:8]2[N:9]([CH3:13])[C:10](=[O:12])[O:11][C:7]=2[CH:6]=[C:5]([N:14]2[CH2:18][C@H:17]([C:19]([NH2:1])=[O:20])[O:16][C:15]2=[O:23])[CH:4]=1
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Solvent: CO
Product: Cn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of ammonia in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-1,3-oxazolidine-5-carboxylate (Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.13 g, 55%); MS for C12H10FN3O5 m/z 296 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.50 (d, 1H), 7.42 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][O:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:10](=[O:12])[CH2:9][O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: COc1ccc(COCC(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COCC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorganic and Medicinal Chemistry Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (17 g, 0.038 mol) followed by TEA (9.7 mL, 0.070 mol). The resulting mixture was stirred overnight at room temperature. The solution was then washed with water, 0.5 M HCl, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product (5.75 g, 69%).
Reaction SMILES: [ClH:1].C([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[C:18]3[CH:31]=[CH:32][CH:33]=[CH:34][C:17]2=3)[CH2:8]1)=[O:6])C.Cl>C(O)C.[OH-].[Na+]>[ClH:1].[CH:30]1[C:19]2[C:18]3[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=3[N:16]([CH2:15][CH2:14][CH2:13][N:9]3[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[CH2:8]3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]=2[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCN2c3ccccc3-c3ccccc3-c3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCN2c3ccccc3-c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
The above ester (0.13 g, 0.27 mmol) was dissolved in ethanol (3 ml) and 2N sodium hydroxide (0.6 ml). The mixture was stirred at room temperature for 1.5 hour, acidified by addition of 1N hydrochloric acid (pH 1) and ethanol was removed in vacuo. The aqueous solution was diluted with water (10 ml), washed with diethyl ether (20 ml) and extracted with dichloromethane (30 ml). The organic extract was dried (MgSO4) and concentrated in vacuo to afford 90 mg (74%) of the title compound as a solid.