Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C)C=O.[Cl:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cc(Br)cc2cc[nH]c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole in 140 ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) of N-chlorosuccinimide followed by stirring at room temperature overnight. A 10% aqueous solution of sodium thiosulfate was added thereto followed by extracting with ethyl acetate. The organic layer was washed with water and brine successively, dr dried over magnesium sulfate and concentrated to dryness to give 14.84 g of the title compound.
Reaction SMILES: F[C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15].CC(C)([O-])C.[K+]>O.Cl>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COCCOc1cccnc1C(=O)O
Reaction time: 18 h
Yield: 26 %

Procedure:
3-Fluoropyridine-2-carboxylic acid (150 mg, 1.06 mol), 2-methoxyethanol (1.5 mL) and potassium tert-butoxide (356 mg, 3.18 mmol) were charged to a sealed tube under nitrogen then stirred at 100 C for 18 h. The mixture was then diluted with water (3 mL), 1M HCl was added to bring the solution to pH 5 and the mixture was extracted with DCM (2×5 mL). 1M HCl was added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (2×5 mL). The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a brown gum (54 mg, 26%). Method C HPLC-MS: MH+ requires m/z=198. Found: m/z=198, Rt=0.29 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[CH:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:12][C:9]4[CH:10]=[CH:11][C:6]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:7][CH:8]=4)=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Oc1ccc(-c2ccsc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-c5ccsc5)cc4)ncnc32)CC1
Temperature: 160 °C
Yield: 23.5 %

Procedure:
A mixture of 4-thiophen-3-yl-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 16 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-thiophen-3-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 22%) as a white solid. Mass spectrum MH+=478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:34]5[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=5)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(-c2cccnc2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 120 °C
Yield: 82 %

Procedure:
To a 25 mL microwave reaction tube was charged 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine (150 mg, 0.274 mmol), 3-pyridinylboronic acid (33.7 mg, 0.274 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11.19 mg, 0.014 mmol), and sodium carbonate (58.1 mg, 0.548 mmol) followed by dioxane (5 mL), and water (1 mL). The reaction was heated at 120° C. for 30 min in microwave reactor. Ethyl acetate (20 mL) was added and the layers were separated. The organic layer was washed with brine, concentrated, and the residue purified by silica gel chromatography (0%-100% EtOAc in hexanes). Product came out at 100% EtOAc, the fractions with the product was combined, evaporated to dryness to afford the title compound as a light gray solid (112 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (d, J=2.0 Hz, 1H) 8.62 (dd, J=4.8, 1.3 Hz, 1H) 8.04-8.18 (m, 2H) 7.97 (s, 1H) 7.56 (dd, J=7.6, 4.8 Hz, 1H) 7.51 (s, 1H) 7.39 (s, 1H) 7.14-7.32 (m, 4H) 5.64 (br. s., 2H) 4.32 (t, J=8.3 Hz, 2H) 3.97 (s, 2H) 3.29 (t, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:48](=[O:49])[C@H:40]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
300 mg (0.702 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 223 mg (0.842 mmol) of (S)-N-tert.-butyloxycarbonyl-phenylalanine, 214 mg (0.842 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 215 μl (1.54 mmol) of triethylamine. The title compound is obtained as mixture of diastereomers in the form of a yellow oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.37, FD-MS: M+ =674.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]1[C@@H:13]([OH:14])[CH2:12][C@H:11]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:9]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:60]([C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1)([O-:62])=[O:61].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:60]([C:63]1[CH:64]=[CH:65][C:66]([C:67]([O:14][C@@H:13]2[CH2:12][C@H:11]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:10]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:9]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:8]2[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:40])=[O:68])=[CH:70][CH:71]=1)([O-:62])=[O:61]
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl((1S,2R,3R,4R,6S)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-6-hydroxycyclohexyl)carbamate (3.20 g, 5.85 mmol), triphenylphosphine (1.92 g, 7.31 mmol) and 4-nitrobenzoic acid (1.37 g, 8.19 mmol) in anhydrous THF (50 mL), at 0° C., was added DIAD (1.42 g, 7.02 mmol) slowly. After addition the mixture was stirred at room temperature for 3 h. The solvent were evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording the title compound as a white solid (2.80 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.26-8.20 (m, 4H), 7.33-7.25 (m, 15H), 4.90-4.86 (m, 3H), 4.71 (d, J=11.3 Hz, 1H), 4.57 (d, J=10.8 Hz, 1H), 4.45 (s, 2H), 4.24 (d, J=9.7 Hz, 1H), 3.97-3.93 (m, 1H), 3.68-3.63 (m, 2H), 3.49 (dd, J=2.0, 8.8 Hz, 1H), 3.38 (t, J=10.1 Hz, 1H), 2.22-2.17 (m, 1H), 1.84-1.76 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:36](Br)[CH3:37].Cl>O1CCCC1.ClCCl.O>[CH2:36]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[CH3:37]
Reactant: CCBr
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1COc2ccc(C(=O)OC)cc2C(CC)(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
0.030 ml (1.1 equivalents) of 1,3-dimethylpropyleneurea and then 0.246 ml (1.1 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 80 mg (0.22 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, in solution in 2.2 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After stirring for 15 minutes, 0.0185 ml (1.1 equivalents) of ethyl bromide is added. After stirring for 5 minutes, water, 1N hydrochloric acid and dichloromethane are added. After separating the organic and aqueous phases, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 25/75) to give 56 mg (58%) of methyl 5-ethyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of an oil; 1H NMR (300 MHz, CDCl3): 0.97 (t, J=7.3 Hz, 3H), 2.41 (q, J=7.3 Hz, 2H), 3.83 (s, 3H), 4.28 (d, J=14.7 Hz, 1H), 4.58 (d, J=14.7 Hz, 1H), 4.86 (s, 1H), 5.02 (s, 1H), 6.82 (d, J=8.5 Hz, 1H), 7.35 (m, 5H), 7.85 (dd, J=8.46 and 2 Hz, 1H), 8.08 (d, J=2.07 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:23])=[CH:24][CH:25]=1
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)O)cc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]benzoic acid Stereoisomer A (75 mg, 0.21 mmol), tetrahydropyran-4-amine (64 mg, 0.63 mmol) and triethylamine (0.12 mL, 0.83 mmol) in N,N-dimethylformamide (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was then partitioned between dichloromethane and saturated sodium bicarbonate in water. The organic layer was separated, concentrated and purified by preparative HPLC to give 4-(((3S)-3-methyl-1,1-dioxido-6-phenyl-1,2-thiazinan-2-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide Stereoisomer A (66.4 mg, 0.15 mmol, 72% yield). 1H NMR (400 MHz, DMSO) δ 8.27-8.19 (d, J=7.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.50-7.43 (m, 4H), 7.43-7.34 (m, 3H), 4.64-4.53 (m, 1H), 4.47-4.33 (m, 2H), 4.18-4.06 (m, 1H), 4.06-3.93 (m, 1H), 3.91-3.81 (m, 2H), 3.46-3.33 (m, 2H), 2.48-2.37 (m, 1H), 2.17-2.08 (m, 1H), 1.92-1.69 (m, 3H), 1.70-1.50 (m, 3H), 1.11-1.02 (d, J=6.9 Hz, 3H); LCMS [M+1]+=443.2.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)=[N:27][CH:28]=1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(CO)c(C)o2)nc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (1.9 g), 2-bromo-5-methoxypyridine (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.0 g, 65%) as a white crystal.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[CH3:19].[OH-].[Na+].CN([CH:25]=[O:26])C>O>[CH3:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:25]=[O:26])[C:9](=[O:18])[N:8]1[CH3:19]
Reactant: Cn1c(-c2ccccc2)cc(=O)n1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)c(C=O)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
N,N-Dimethylformamide (3.4 mL, 43.6 mmol) was added to a flask under nitrogen atmosphere. After cooling to 0° C., phosphorus oxychloride (1.4 mL, 15.2 mmol) was added. The resulting reaction mixture was stirred at room temperature for 50 minutes. The resulting reaction mixture was transferred to a reaction flask containing a solution of 1,2-dimethyl-5-phenyl-1H-pyrazol-3(2H)-one (820 mg, 4.36 mmol) in DMF (4.9 mL). The reaction flask was immersed in a preheated oil bath (120° C.) and, after stirring for 12 minutes, cooled to room temperature. 5 N NaOH (15 mL) was added to the cooled reaction mixture. After diluting with icy water, the mixture was extracted with chloroform. The organic layer was dried with sodium sulfate and then filtered. The filtrate was concentrated. After diluting DMF remaining in the resulting residue again with chloroform and then washing with water, the aqueous layer was extracted again with chloroform. The organic layer was collected, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The concentrated residue was subjected to the next step without further purification.
Reaction SMILES: [C:1]1(C)[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:9](Cl)(Cl)(Cl)[Cl:10]>>[Cl:10][Si:9].[C:6]1([OH:7])[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Cc1ccccc1O
Reactant: Cl[Si](Cl)(Cl)Cl
Product: Oc1ccccc1
Product: [Si]Cl
Reaction time: 5 h

Procedure:
About 1 mol of fine granular hydrated silica, 0.5 mol of cresol and 1 mol of silicon tetrachloride are slowly added simultaneously while agitating and keeping the temperature below the boiling temperature for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing a phenol chlorosilicon acid resinous product. To this resinous product about 1 mol of a ketone, acetone, is slowly added while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing granules of organic silicon acid resinous product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OCC)(=O)[C:12]([O:14]CC)=[O:13].[O-]CC.[Na+].C(OCC)C>C(O)C>[O:10]=[C:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:11]([C:12]([OH:14])=[O:13])=[CH:9]1
Reactant: CC(=O)c1ccccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1cc(=O)c2ccccc2o1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
2'-hydroxyacetophenone (25.7 g) and diethyl oxalate (33.1 g) were added to a solution of sodium ethoxide in ethanol (prepared from 13.0 g of sodium and 375 ml of ethanol), and the mixture was heated for 1 hour while refluxing. After the reaction mixture was cooled to room temperature, ethyl ether (500 ml) was added, and the separating crystals were collected by filtration. To this crystal, 2N hydrochloric acid (600 ml) was added, followed by ethyl ether extraction. The ethyl ether layer was washed with water and dried (MgSO4), after which it was concentrated under reduced pressure. The residual oily substance was dissolved in acetic acid-concentrated hydrochloric acid (1:1,200 ml) and heated for 1 hour while refluxing. The reaction mixture was poured over water (1 liter); the separated crystals were collected by filtration and then washed by sequential additions of water, ethanol and ethyl ether in that order, to yield 4-oxo-4H-1-benzopyran-2-carboxylic acid (83.5%), which was then recrystallized from ethanol to yield colorless needles having a melting point of 240° to 241° C. (decomposed).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH2:41][NH2:42]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:10][C@H:9]1[C:24]([NH:42][CH2:41][C:37]1[O:36][CH:40]=[CH:39][CH:38]=1)=[O:26])(=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: NCc1ccco1
Product: COc1ccc(CON=C2C[C@@H](C(=O)NCc3ccco3)N(C(=O)c3ccccc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, benzoyl chloride and 2-furylmethylamine the title compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=448.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:47][N:48]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH2:52][NH:51][CH2:50][C:49]1=[O:59]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:51]1[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[N:48]([CH3:47])[C:49](=[O:59])[CH2:50]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CN1C(=O)CNCc2ccccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1C(=O)CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (80 mg, 0.24 mmol) in dry DCM (10 mL), was added HOBT (42 mg, 0.31 mmol), EDC (59 mg, 0.31 mmol) and DIPEA (0.20 mL, 1.2 mmol). The reaction mixture was stirred at r.t. for 10 min. A solution of 1-methyl-1,3,4,5-tetrahydrobenzo (e) [1,4]diazepin-2-one trifluoroacete (70 mg, 0.24 mmol) in dry DCM (5 mL) was added and the reaction mixture was stirred at r.t. overnight. After the completion of the reaction, as confirmed by TLC, the crude product was extracted with DCM (10 mL) and washed sequentially with 10%. HCl solution (10 mL) and saturated solution of sodium bicarbonate (10 mL). The organic layer was separated and washed with brine and dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet.Ether) to afford 2 [3-(1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-(R)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (95 mg, 78%) as viscous oil.