Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:4][C:3]=1[S:8]([C:11]([F:12])([F:13])[F:14])(=[O:9])=[O:10]
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2CCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10.00 g, 38.31 mmol) in tetrahydrofuran (150 mL) was treated with 3-bromo-1-propanol (15.98 g, 114.93 mmol) and triphenylphosphine (20.1 g, 76.62 mmol). Diethylazodicarboxyate (13.34 g, 76.62 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 min, after which the ice bath was removed and was stirred for 30 minutes at room temperature. The reaction mixture was partially concentrated and ethyl acetate (200 mL) was added. The precipitate was filtered and the filtrate was concentrated to dryness. The crude compound was purified by flash chromatography on silica gel using 100% ethyl acetate as the eluent. The afforded 7.8 g (53%) of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.230 (s, 1H), 4.419-4.385 (t, 2H), 3.530-3.498 (t, 2H), 2.370-2.304 (q, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 422.9.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:17]=[O:18])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.CCOCC.O>[C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH2:17][O:18][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-acetoxy-2-formyl-4-methoxyhydrocinnamate (3.31 g) and imidazole (2.42 g) in methylene chloride (25 ml) is added a solution of tert-butylchlorodimethylsilane (2.73 g) in methylene chloride (25 ml). The mixture is stirred at room temperature for about 60 minutes, diluted with ether and water, and the organic layer washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][S:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:27])=[O:26].CN(C)C(N(C)C)=N>CS(C)=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][S:25]([CH3:24])(=[O:26])=[O:27])[CH2:35][CH2:34]3)[N:7]=1)=[N:9]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCS(C)(=O)=O)CC4)n3)nc2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a solution of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.664 mmol) in DMSO (1.5 mL) under nitrogen was added 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (0.265 g, 0.996 mmol) and 1,1,3,3-tetramethylguanidine. The reaction was stirred at 80° C. for 18 h. After that time the reaction was cooled to rt, diluted with ethyl acetate (50 mL), washed with water (2×20 mL), brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one (0.120 g, 38%) as a yellow solid: mp 243-244° C.; 1H NMR (400 MHz, CDCl3): δ 10.28 (br s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.73-7.66 (m, 1H), 6.87-6.81 (m, 2H), 6.49 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.69-3.61 (m, 4H), 3.23 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 2.98 (t, J=6.4 Hz, 2H), 2.72-2.64 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.ClCCl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([Cl:27])=[O:23])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of N,N-dimethylformamide (DMF) was added to a solution of 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyric acid (3.53 g, 11.3 mmol, 1.0 eq) in dichloromethane (55 mL). Oxalyl chloride (3.0 mL, 33.9 mmol, 3.0 eq) was added dropwise over 5 minutes to the reaction mixture, which was subsequently stirred for 2 hours at ambient temperature. The mixture was concentrated under reduced pressure to provide 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyryl chloride.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[C:20]([O:19][CH3:18])=[O:21])[CH2:13]1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: c1ccc2sc(OCC3CCCNC3)nc2c1
Product: COC(=O)c1cccc(N2CCCC(COc3nc4ccccc4s3)C2)c1
Yield: 19.7 %

Procedure:
Using 3-[(benzothiazol-2-yl)oxymethyl]piperidine (58.0 mg, 0.234 mmol) and 3-(methoxycarbonyl)phenylboric acid (84.2 mg, 0.468 mmol), the same procedure was followed as in Example 2 to give 17.6 mg (20%) of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]2[NH:11][CH:12]=[CH:13][C:4]=12.C([O-])([O-])=O.[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:6]1[CH:7]=[C:8]([CH:9]=[O:10])[C:3]([NH:2][CH3:1])=[C:4]2[CH:13]=[CH:12][N:11]=[C:5]12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNc1c(C=O)cnc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1c(C=O)cn(Cc2ccccc2)c2nccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 4-methylamino-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.5 g, 2.86 mmol) in DMF is added Na2CO3 (900 mg, 8.6 mmol) and benzyl bromide (0.5 ml, 4.3 mmol). The reaction is stirred at room temperature for 12 hours. The reaction mixture is partitioned in 100 ml water and 100 ml ethyl acetate, extracted with ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by silica gel flash chromatography, eluted with 5% methanol in ethyl acetate to give the title compound as yellow solid. 1H NMR 400 MHz (DMSO-d6) δ 9.70 (s, 1H), 9.20 (q, 1H, J=5.2 Hz), 8.59 (s, 1H), 7.46 (m, 2H), 7.35 (m, 3H), 7.28 (d, 1H, J=2.8 Hz), 7.22 (d, 1H, J=2.4 Hz), 5.65 (s, 2H), 3.31 (d, 2H, J=2.4 Hz). MS m/z 266.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1

Procedure:
6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (0.032 g, 0.14 mmol) was solubilised in dry dioxane (2 mL). Thionyl chloride (0.081 mg, 0.14 mmol) was added drop-wise and the reaction mixture heated at reflux for 1.25 h. The reaction mixture was concentrated, and then re-concentrated from DCM to give 6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride which was used directly in step 2
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[C:1]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1

Procedure:
After benzoic acid (300.6 mg, 2.46 mmol), triphenylphosphine (776.2 mg, 2.95 mmol), (2R,4R)-2,4-pentanediol (309.1 mg, 2.95 mmol), and THF (12 mL) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.55 ml, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for ix hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 525.3 mg of a colorless oily substance. Measurement of 1H-NMR showed that 380 mg of (4S,2R)-4-benzoyloxypentane-2-ol (yield: 74%/benzoic acid), and 146 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C([N:43]1[CH2:48][CH2:47][CH:46]([CH:49]=O)[CH2:45][CH2:44]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:53])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:53])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:49][CH:46]2[CH2:47][CH2:48][NH:43][CH2:44][CH2:45]2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(CC2CCNCC2)C[C@@H]1CCCB(O)O
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and N-boc-piperidine-4-carboxaldehyde (149 mg, 0.7 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-4-ylmethyl)pyrrolidine-3-carboxylic acid (66 mg, 31%) as a granular amber solid. NMR (D2O) δ 3.70-4.00 (m, 2 H), 3.30-3.45 (m, 4 H), 3.25 (d, J=7 Hz, 2 H), 2.92 (br t, J=13 Hz, 2 H), 2.50-2.65 (m, 1 H), 2.00-2.15 (m, 1 H), 1.85-2.00 (m, 2 H), 1.50-1.65 (m, 1 H), 1.35-1.50 (m, 2 H), 1.15-1.35 (m, 3 H), 0.65-0.75 (m, 2 H). MS (m−H2O+1): 296.3; MS (m−2 H2O+1): 278.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13](Br)=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([NH:21][CH:18]([CH3:20])[CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cnn(-c2ncc(Cl)cc2Cl)c1Br
Solvent: ClCCl
Product: CC(C)Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A mixture of 5.1 g (0.015 mol) of 1-(3,5-dichloropyrid-2-yl)-4-nitro-5-bromopyrazole and 13.4 g (0.225 mol) of isopropylamine in 100 ml of methylene chloride is stirred at room temperature for 20 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in 50 ml of methylene chloride and washed twice with 50 ml of water; the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is crystallized by rubbing with petroleum ether, filtered off by suction and dried. 4.0 g (84.4% of theory) of 1-(3,5-dichloropyrid-2-yl)-4-nitro-5-isopropylaminopyrazole with a melting point of 123° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCOC(C)=O.O>[O:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:1][C:2]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:32][CH2:33]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1ccc(OCc2ccccn2)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccn2)cc1OCCN1CCOCC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
To 1.0 g of 2-hydroxy-4-(2-pyridylmethoxy)benzaldehyde were successively added 30 mL of acetonitrile, 4.26 g of cesium carbonate and 0.85 g of 4-(2-chloroethyl)morpholine hydrochloride. The mixture was stirred at 90° C. for 2 hours. To the reaction mixture, 50 mL of water and 150 mL of AcOEt were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated to give 1.56 g of the title compound in quantitative yield.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:15][CH2:14][C@@:13]3([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[C@@H:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]3)[CH2:7]2)[CH2:4][CH2:3]1.[CH2:25]([N:27]([CH2:42][CH3:43])[C:28](=[O:41])[C:29](=[N:33]NC1C=CC=CC=1)[C:30](=O)[CH3:31])[CH3:26].CC(O[Na])=O>[Zn].C(O)(=O)C>[ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:15][CH2:14][C@:13]3([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[C@H:8]([CH2:9][C:10]4[C:30]([CH3:31])=[C:29]([C:28]([N:27]([CH2:42][CH3:43])[CH2:25][CH3:26])=[O:41])[NH:33][C:11]=4[CH2:12]3)[CH2:7]2)[CH2:4][CH2:3]1
Reactant: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Reactant: COc1cccc([C@]23CCN(CC4CC4)C[C@@H]2CCC(=O)C3)c1
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(CC3CC3)CC[C@@]1(c1cccc(OC)c1)C2
Yield: 57.9 %

Procedure:
0.28 g (0.80 mmol) of (±)-trans-2-cyclopropylmethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.56 g (2.14 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.131 g (1.6 mmol) of CH3COONa, 0.402 g (6.16 mmol) of zinc dust and 10 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography ((i-Pr)2O/MeOH/conc. NH4OH 90:10:0.5). The product was dissolved in acetone and the solution brought to acidic pH with Et2O/HCl . The solid was filtered, washed and dried yielding 0.225 g of the title compound. M.p.=190°-195° C.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[C:7]([S:15]([NH:18]C(C)(C)C)(=[O:17])=[O:16])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)=[O:5])[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([S:4]([C:6]1[C:7]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)c1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)c1csc(C(=O)OC)c1S(N)(=O)=O
Yield: 93.3 %

Procedure:
A solution of 2.2 g of 4-propylsulfinyl-3-(N-(1,1-dimethylethyl)aminosulfonyl)-2-thiophenecarboxylic acid, methyl ester in 15 mL methylene chloride was treated with 30 mL trifluoroacetic acid at room temperature for 24 hours. The solvent were removed in vacuo and the residue was crystallized with butyl chloride to give 1.74 g white solid; m.p. 131°-144° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H:30](CNC1C=CC=CC=1[N+]([O-])=O)[C:31]([OH:33])=[O:32])=O)(C)(C)C.[CH3:45]O>[Pd]>[CH3:45][O:33][C:31](=[O:32])[CH2:30][N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]1=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 4 h

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-(2-aminophenyl-amino)-propionic acid. A mixture of (2S)-2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of MeOH under hydrogen at 1 atmosphere was stirred for 4 h. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford the 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification: 1H NMR (CD3OD) δ 6.75-6.70 (3H, m), 6.65-6.58 (1H, m), 4.35-4.3 1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:11]([OH:13])=O)[N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:37]([O:39][C:40](=[O:59])[C@H:41]([CH3:58])[CH2:42][C@H:43]([NH2:57])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)[CH3:38].C(N(CC)CC)C>CN(C=O)C.O>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:47]=[CH:46][C:45]([CH2:44][C@@H:43]([NH:57][C:11]([C:4]2[N:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)=[O:13])[CH2:42][C@H:41]([C:40]([O:39][CH2:37][CH3:38])=[O:59])[CH3:58])=[CH:50][CH:49]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(=O)O)nc(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)O)nc(O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxypyrimidine-4,6-dicarboxylic acid (71 mg, 0.39 mmol) in DMF (10 mL) is added HOBT (59 mg, 0.39 mmol) and EDCl (74 mg, 0.39 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 1) (120 mg, 0.35 mmol) and triethylamine (0.15 ml, 1.16 mmol) are added. After stirring the mixture at room temperature for five hours, water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound. HPLC retention time 1.32 minutes (condition C); MS 478.3 (M+H); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.05-1.07 (d, J=7.07 Hz, 3H), 1.09-1.12 (t, J=7.07 Hz, 3H), 1.72-1.79 (m, 1H), 1.81-1.89 (m, 1H), 2.44-2.49 (m, 1H), 2.77-2.82 (m, 1H), 2.89-2.95 (m, 1H), 3.95-4.01 (q, J=7.07 Hz, 2H), 4.16-4.26 (m, 1H), 7.26-7.28 (m, 2H), 7.31-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 8.73-8.76 (d, J=9.35 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.210 g, 0.760 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert-butyl {[2-(aminooxy)ethyl]carbamoyl}carbamate 84 (0.250 g, 1.140 mmol), 1-hydroxybenzotriazole (0.154 g, 1.140 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.218 g, 1.140 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 85 (0.31 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)CCl>[OH:17][C:16]1[C:15]2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:3])([CH3:1])[C:14]=2[CH:13]=[C:12]([CH3:18])[CH:11]=1
Reactant: Cc1cccc(O)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2,5-Dimethyl-2,5-dichlorohexane (183 g, 1 mol) was stirred with m-cresol (129.6 g, 1.2 mol) and aluminum chloride (4 g) was added in one portion. The mixture was heated at 95° C., with stirring for 1.5 h, after which ethylene dichloride (100 mL) was added and then the heating was continued. After 1 h the mixture was cooled to 20° C. and poured onto an ice-water/hydrochloric acid mixture (150 mL, 10% HCl solution). The mixture was then extracted with toluene (500 mL). The organic layer was separated, washed with brine (3×50 mL) and dried (Na2SO4). The solvent was removed by distillation and the residue was crystallized from a hexane/benzene solvent mixture to give 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (171 g), mp 133°-134° C., GLC purity 99%+. 1H-NMR (CDCl3) δ6.82 (1H, broad s), 6.35 (1H, d, J= 1.4 Hz), 4.72 (1H, s), 2.30 (3H, s), 1.71 (4H, m), 1.49 (6H, s), 1.34 (6H, s). 13C-NMR (CDCl3) δ154.2 (1C, s), 147.8 (1C, s), 135.7 (1C, s), 128.0 (1C, s), 120.2 (1C, d), 114.6 (1C, d), 37.9 (1C, t), 35.2 (1C, t), 34.6 (1C, s), 33.7 (1C, s), 32.0 (2C, q), 28.5 (2C, q), 20.8 (1C, q). IR (KBr) 3,503 cm-, MS (m/e) 218 (M+, 24.7), 203 (100.0), 161 (55.1), 147 (23.9), 57 (10.9).