Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3](=[O:17])[CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)[NH2:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[C:21]([F:28])[CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:2][NH:1][C:3](=[O:17])[CH2:4][C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6]2)=[O:27])=[C:21]([F:28])[CH:20]=1
Reactant: O=C=Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NN)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-(2-hydrazino-2-oxoethyl)-1-pyrrolidinecarboxylate (6.58 mmol) in dichloromethane (15 mL) was cooled to 0° C. and was treated drop-wise with 4-bromo-2-fluoro-1-isocyanatobenzene (6.58 mmol). The reaction was allowed to warm to room temperature, and after ˜30 min a white solid had formed. The reaction contents were concentrated to dryness in vacuo. No further purification was carried out on the resulting white solid (3.01 grams, 100%). MS(ES)+ m/e 459/461 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH2:10][CH:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[CH2:10][CH:9]([CH3:11])[CH2:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1Cc2nc(N)[nH]c(=O)c2C1
Product: CC1Cc2nc(N)nc(Cl)c2C1
Yield: 34 %

Procedure:
Compound 2 (297 mg, 1.8 mmol) and phosphorus oxychloride (15 mL) were heated to reflux for 3 h. The reaction mixture was cooled and evaporated at reduced pressure, and the residue was diluted with chloroform (50 mL) and neutralized with ammonium hydroxide slowly in an ice bath. The organic portion was washed with water (3×30 mL). Solvents were evaporated at reduced pressure, and the residue was purified by column chromatography using chloroform/hexane (4/1) as eluent to afford 112 mg (34%) of 3 as a white-off solid TLC Rf0.48 (CHCl3/CH3OH, 10:1); mp: 181.5-182.9° C., 1H NMR (DMSO-6): δ 1.16-1.18 (d, 3 H, CH3), δ 1.55-1.65, 2.15-2.38, 2.49-2.62, 2.83-2.92 (m, 5 H, CH2CHCH2), δ 6.83 (br, 2H, NH2, exch). Anal. (C8H10ClN3) C, H, N, Cl: calcd, 52.32, 5.49, 22.88, 19.31; found, 52.33, 5.62, 22.63, 19.09.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=1>>[F:41][C:32]1[CH:31]=[C:30]([C:17]2[CH:16]=[CH:15][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:13])=[CH:19][CH:18]=2)[CH:35]=[CH:34][C:33]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1F

Procedure:
The title compound is prepared starting with (2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone and N-(4-Bromo-2-fluoro-phenyl)-methanesulfonamide following a procedure significantly analogous to Procedure FF. MS (m/e): 446.2 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([CH2:28][CH2:29][O:30][CH3:31])[N:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C>Cl.CO>[C:32]([C:24]1[N:23]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]3)[CH2:17][CH2:18]2)[CH:27]=[C:26]([CH2:28][CH2:29][O:30][CH3:31])[N:25]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)CC2)nc(C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-[4-(2-{4-[2-tert-Butyl-6-(2-methoxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (900 mg, 1.680 mmol) was dissolved in 4 M HCl/MeOH (25 ml). The resulting solution was stirred at about 25° C. for about 16 h. The solvent was removed under reduced pressure to provide the title compound (690 mg, 1.539 mmol, 92% yield) as a colorless solid, which was used in the next step without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2>CO.C(O)(=O)C.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: N#Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Reaction time: 36 h
Yield: 7.3 %

Procedure:
To the solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide) (311 mg) in methanol and acetic acid (1: 1,10 mL) a catalytic amount of 10% Pd-C was added and the mixture was hydrogenated at 50 p.s.i. for 36 hr. The mixture was filtered through a pad of celite. The residue was purified first by flash chromatography using 5–20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase IHPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (23 mg); MS (ES+) 342 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:12]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[NH:7][C:6]=3[CH:11]=2)=[O:27])[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O
Product: O=C(Nc1ccc2oc(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-3H-benzoxazole-2-one and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 2. Melting Point: 187-190° C. (water)
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:29]>>[ClH:29].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]2=1
Reactant: CC(=O)c1ccc2c(c1)C1CC2CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)C1CNCC2C1
Temperature: 70 °C

Procedure:
4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (190 mg, 0.63 mmol) was treated with excess 3N HCl ethyl acetate and warmed to 70° C. for 1 hour then concentrated and dissolved in a minimum of methanol. The resulting solution was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (81 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (br s, NH), 7.89 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (br s, NH), 7.44 (d, J=8.0 Hz, 1H), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br m, 2H), 2.54 (s, 3H), 2.17 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). GCMS m/e 201 (M+). M.p. 198–202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](CCl)=[CH:7]2.[C-]#N.[Na+].[CH3:17][C:18]#[N:19]>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:17][C:18]#[N:19]
Reactant: ClCc1ccc2c(Cl)cccc2c1
Reactant: CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1cccc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 5-chloro-2-chloromethylnaphthalene (1.37 g crude product, 5.12 mmol), NaCN (0.275 g, 5.61 mmol), CH3CN (10 mL), and H2O (1 mL) was heated under reflux for 5.5 hours, cooled, and stirred at room temperature overnight. The mixture was partitioned between ether and H2O. The aqueous phase was extracted with ether, and the combined ether layers were washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (eluant EtOAc/hexane (10:90)) gave a pale yellow solid (600 mg, 58%), m.p. 95°-98° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1>>[N+:1]([C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:6]([F:15])([F:5])[F:14])[CH:8]=1)([O-:4])=[O:2]
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: O=[N+]([O-])O
Product: O=c1[nH]cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 75 h

Procedure:
To 0.95 l. of stirred fuming nitric acid was added 29 g. of 5-trifluoromethyl-2-pyridone over 1 hour, and stirring was continued for 75 hours. The fuming nitric acid was evaporated and the residue was triturated with acetone. The acetone was evaporated to about 60 ml. and the precipitate was collected on a filter and washed with a 5:1 mixture of methylene chloride:acetone and dried and used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:29])[C:11]([N:14]2[C:19](=[O:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH2:27]Br)[O:16][CH2:15]2)([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[C:32]([O-:35])(=[O:34])[CH3:33].[Na+]>CN(C)C=O.CCOCC>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:29])[C:11]([N:14]2[C:19](=[O:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH2:27][O:35][C:32](=[O:34])[CH3:33])[O:16][CH2:15]2)([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Yield: 77.6 %

Procedure:
A mixture of N-(3-trifluoromethylphenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.09 g) and sodium acetate (0.36 g) was heated at 80-90° C. in N,N-dimethylformamide for 3 hours. The cooled solution was diluted with ether, washed with water, dried (magnesium sulphate) and evaporated in vacuo to give N-(3-trifluoromethylphenyl)-2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 103, 0.81 g) as a white solid, m.p. 76.5-77.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][CH2:25][OH:26])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:60]([O:67][C:68]1[CH:78]=[CH:77][CH:76]=[C:75](O)[C:69]=1[C:70]([N:72]([CH3:74])[CH3:73])=[O:71])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][CH2:25][O:26][C:75]3[CH:76]=[CH:77][CH:78]=[C:68]([O:67][CH2:60][C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:69]=3[C:70](=[O:71])[N:72]([CH3:73])[CH3:74])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1c(O)cccc1OCc1ccccc1
Reactant: COC(=O)c1cc2cc(OCCO)ccc2cc1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OCCOc3cccc(OCc4ccccc4)c3C(=O)N(C)C)ccc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-benzyloxy-7-(2-hydroxyethoxy)-naphthalene-2-carboxylic acid methyl ester (239 mg, 0.68 mmol), triphenylphosphine (445 mg, 1.70 mmol) and DIAD (0.334 mL, 1.70 mmol) in THF (10 mL) is stirred at RT for 15 min. Then 2-benzyloxy-6-hydroxy-N,N-dimethylbenzamide (460 mg, 1.70 mmol) in THF (8 mL) is added drop wise and the mixture is stirred at RT for 18 h. The solvent is removed and the residue is purified to give the title compound.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:10]>CC#N.CCOC(C)=O>[I:1][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12]([O:11][CH2:9][CH3:10])=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)/C=C/c1ccc(B(O)O)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(I)cc1
Reaction time: 26 h
Yield: 86.1 %

Procedure:
N-Iodosuccinimide (2.5 g, 11 mmol) was added to a suspension of 4-(E-3-ethoxy-3-oxo-1-propen-1-yl)phenylboronic acid (2.2 g, 10 mmol) in CH3CN (50 mL) at room temperature. The reaction was covered with foil, stirred for 26 h, and then diluted with EtOAc. The resulting mixture was washed with water (2×100 mL), washed with sodium thiosulfate (100 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give 2.6 g of (E)-ethyl 3-(4-iodophenyl)acrylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 2H), 7.60 (d, 1H), 7.53 (d, 2H), 6.68 (d, 1H), 4.19 (q, 2H), 1.26 (t, 3H); LCMS: 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20]3=[O:31])[C:6](=[O:32])[N:5]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:4]=2[N:3]=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:20]3=[O:31])[C:6](=[O:32])[N:5]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCN1CCC(Cc3ccccc3)C1=O)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCN2CCC(Cc3ccccc3)C2=O)c(=O)c2[nH]c(Cl)nc21
Reaction time: 4 h

Procedure:
A solution of 8-chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.35 g, 0.67 mmol), Pd(PPh3)4 (0.082 g, 0.07 mmol) and morpholine (0.6 ml, 6.7 mmol) in THF (10 ml) was degassed (sequential evacuation followed by addition of nitrogen×3) then stirred for 4 h. The solution was then loaded onto an aminopropyl SPE (5 g) and eluted first with MeOH then 5% AcOH/MeOH to provide the title compound containing a small impurity. Further purification over silica (10 g SPE, gradient elution ether/ethyl acetate 1:0 to 0:1) provided the title compound as a clear oil (0.10 g, 31%).
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].Br[CH2:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:1][S:2][CH:3]1[N:6]([CH2:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: O=C(CBr)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of 4-methylthioazetidin-2-one (Clauss K, Grimm D, Prossel G, Anal, 1974, 539) (1.17 g, 0.01 mol) in THF (lOml) was added dropwise over 5 minutes to a suspension of sodium hydride (0.42 g, 0.01 mol) in dry THF (30 ml) under a nitrogen atmosphere at -10° C. The mixture was stirred for 15 minutes whilst keeping the temperature between -5 and -10° C. 1-Bromo-4-phenylbutan-2-one (Tetrahedron, 1970, 26, 5611) (2.27 g, 0.01 mol) in dry THF (10 ml) was added over 5 minutes at -10° C. The resultant mixture was stirred at room temperature for 1 hour then poured onto ice/water (100 g), filtered through Hyflo, washed with brine and separated. The organic extract was dried and evaporated under reduced pressure to a yellow oil. This was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate 2:1, to give 4-methylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one as a colourless oil (1.08 g, 41%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].[NH3:25].O1CCOCC1>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:21]([NH2:25])(=[O:23])=[O:22])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc2c1Br
Reactant: N
Solvent: C1COCCO1
Product: CC(=O)OCCc1cc(S(N)(=O)=O)c2c([N+](=O)[O-])cccc2c1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Solid 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonyl chloride (5.00 g, 11.45 mmol) was added at room temperature to 0.5M ammonia in dioxane (92 mL, 46 mmol). After stirring at room temperature for 40 minutes, the mixture was evaporated under vacuum to a residue which was mixed with water (100 mL), sonicated, and filtered. The collected pale-yellow solid was washed with water (2×20 mL) and vacuum dried to afford the title compound (4.75 g).
Reaction SMILES: C1C2C(OC([NH:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]3[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]4[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[N:28]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:24][CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1>[NH2:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]1[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]2[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:28]2[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[CH:24][CH:23]=1)=[O:20]
Reactant: C[C@H](NC(=O)OC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of 3.15 g (4.65 mmol) of tert-butyl(2S,5R)-2-{4-[((2S)-2-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanoyl)amino]benzyl}-5-[(R)-hydroxy(pyridin-3-ylmethyl]pyrrolidine-1-carboxylate from step A in 3 mL of anhydrous THF was added 0.396 g (4.65 mmol) of piperidine. The resulting mixture was heated to 35° C. under an atmosphere of nitrogen for 2 h then all volatiles were removed in vacuo to afford the crude title compound which was used without further purification. LC-MS: m/z (ES) 455 (MH)+.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][OH:17])[C:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[F:33])=[C:9]([CH3:34])[N:8]=1.[C:35]([O-])(O)=O.[Na+]>CO.O>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16][OH:17])[C:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:35])=[O:31])=[CH:25][C:24]=2[F:33])=[C:9]([CH3:34])[N:8]=1
Reactant: O=C([O-])O
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1F
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a stirred solution of the product from step (v) (0.08 g) in MeOH (1 mL) and the mixture was heated to 70° C. for 2 h. The mixture was allowed to cool, diluted with water (2 mL) and neutralised with NaHCO3. The aqueous was extracted with EtOAc and the combined organic phase was dried and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.005 g.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(#N)C>[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][N:30]1[CH2:2][C:3]2[C:8](=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=2)[C:9]1=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN1Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Methyl 6-bromomethyl-3-nitrobenzoate (430 mg, 1.64 mmol), N-glycyl-3(R)-methyl-β-alanine benzyl ester hydrochloride 2-4 (611 mg, 2.13 mmol) and triethylamine (0.68 mL, 4.92 mmol) were stirred in acetonitrile (10 mL) for 16 hours. The solution was poured into 1N HCl and extracted with EtOAc (3×), washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography eluting with EtOAc afforded 2-6 as a solid. Rf (silica; EtOAc)=0.45. ##STR60## N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-β-alanine (2-7)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH2:37][CH3:38])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1)([CH2:37][CH3:38])[CH3:36]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 2-bromobutane (0.66 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.85 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][C:16]4[CH:20]=[C:21]([C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])[CH:22]=[CH:23][C:15]=4[NH:14][C:13]=3[CH:31]=2)[CH:5]=[C:4]([F:32])[N:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][C:16]4[CH:20]=[C:21]([C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])[CH:22]=[CH:23][C:15]=4[NH:14][C:13]=3[CH:31]=2)[CH:5]=[C:4]([F:32])[N:3]=1
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)NC(=O)c1ccc(Nc3cc(F)nc(F)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc2c(c1)NC(=O)c1ccc(Nc3cc(F)nc(F)c3)cc1N2
Temperature: 25 °C

Procedure:
A mixture of Example 205A (0.52 g, 1.18 mmol) and LiOH (0.144 g, 6.0 mmol) in 20 mL of THF and 20 mL of H2O was heated under reflux overnight. After the solution cooled to room temperature, the solution was neutralized with 10% HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtrated and concentrated under vacuum to give the title compound. MS (DCI) m/e 425 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.27 (br, 1H), 9.72 (s, 1H), 9.68 (s, 1H), 7.98 (s, 1H), 7.75 (d, J=8.73 Hz, 1H), 7.06 (s, 1H), 6.96-6.99 (m, 3H), 6.74 (dd, J=8.73, 2.18 Hz, 1H), 6.62 (s, 2H), 1.46 (s, 6H).