Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].CN(C)CCCN=C=NCC.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:10]#[N:11]
Reactant: Nc1ccc(F)cc1Br
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
A mixture of 2-bromo-4-fluoroaniline (10.0 g, 52.6 mmol), cyanoacetic acid (5.36 g, 63.1 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide•hydrochloride (15.1 g, 78.9 mmol), 1H-1,2,3-benzotriazol-1-ol (10.6 g, 78.9 mmol), triethylamine (10.9 mL, 78.9 mmol) and N,N-dimethylformamide (150 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a pad packed with NH silica gel. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane and collected by filtration to give the title compound (8.04 g, 59%) as a white solid.
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:26][CH3:27])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:26][CH3:27])=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)ccc1Cl
Yield: 83 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 above and 44.5 g of 2-chloro-5-[2-(2,4-di-tert-amylphenoxy)butyramido]aniline was stirred in an oil bath at 150° C for 3 hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from ligroin to yield 51 g (yield 83%) of Coupler (1) having a melting point of 65° to 68° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]([C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH:15]=1)[OH:14])[CH3:8].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:13]([C:13]1([CH:15]=[C:9]([CH:7]([CH:6]([CH3:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:8])[CH2:10][C:11]([C:11](=[O:16])[CH3:10])([OH:16])[CH:12]1[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][C:25]=1[C:6]([CH3:7])=[CH2:5])[OH:14])(=[O:14])[CH3:12]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C(C)c1ccncc1C1C(O)(C(C)=O)C=C(C(C)C(C)CCCCC)CC1(O)C(C)=O
Temperature: 0 °C

Procedure:
Thionyl chloride (5 ml.) was added dropwise to a stirred solution of 1.27 g. of 1,3-diacetyl-2-{4-[1-hydroxy-1-methyl)ethyl]-3-pyridyl}-5-(3-methyl-2-octyl)resorcinol in 40 ml. of pyridine, cooled in an ice-salt bath at -10°. The mixture was stirred and the temperature was allowed to rise to 0° within 11/2 hours. The mixture was poured into ice water and was extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was chromatographed on a Florisil column (60-100 mesh) using graded methanol/benzene solvent mixtures to give the pure product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:30])(=[O:29])[C:14]=2[CH:31]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:29])(=[O:30])[C:14]=2[CH:31]=1)=[O:9]
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Pyrrolidine (0.14 mL, 1.74 mmol) was added to a solution of Example 56k (0.5 g, 1.16 mmol) in dry DMF (5 mL) in an atmosphere of nitrogen. It was stirred at 100° C. for 5 h. The reaction mixture was concentrated and treated with chilled water to obtain a solid which was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.375 g, (69.44%); 1H NMR (DMSO-d6): δ 1.75 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.85 (m, 2H, CH2), 3.20 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.25 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.20 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (ES−) 463 (M+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][N:9]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O>[F:22][C:2]([F:21])([F:1])[CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:12][CH:11]=2)=[N:8][N:9]=1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: CCCCC(Cc1nnc(-c2ccc(O)cc2)s1)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2nnc(CC(CCCC)C(F)(F)F)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
0.66 g (2 mmol) of 2-(2-trifluoromethylhexyl)-5-(4-hydroxyphenyl)-1, 3, 4-thiadiazole was added to pyridine, 0.50 g (2,5 mmol) of undecanoic acid chloride was dripped while the mixture was cooled, and they were stirred at 50° C. for two hours. After the reaction was completed, water was added, ether extraction was performed, the solution was dried, and the solvent thereof was removed. Then, the solution was refined by column chromatography (toluene: ethyl acetate=6:1) and recrystallization (ethanol), and 0.72 g of a desired material was obtained. ##STR31##
Reaction SMILES: S(C)C.[CH2:4]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C[O:22]CC1>>[CH2:4]([O:11][CH2:12][CH:13]1[O:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: C1=COC(COCc2ccccc2)CC1
Solvent: CSC
Product: OC1CCC(COCc2ccccc2)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
BH3.SMe2 (17 mL, 1 M in THF) was added slowly to a stirred solution of 2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (2.87 g, 14.06 mmol) (13) in THF (100 mL) at −78° C. The resulting mixture was allowed to warm to room temperature overnight. The mixture was quenched by the slow addition of 1M NaOH (50 mL) at 0° C. followed by H2O2 (13 mL, 30% in water). The resulting mixture was stirred for 2 hours at room temperature. After aqueous work up the residue was purified on silica gel using EtOAc and hexane to give 6-(benzyloxymethyl)tetrahydro-2H-pyran-3-ol (14).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH2:18][CH3:19])[CH:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@@H:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[O:4][C@@H:5]1[CH2:18][CH3:19])([CH3:17])([CH3:16])[CH3:15].[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[O:4][C@H:5]1[CH2:18][CH3:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCC(Oc1ccccc1N)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Product: CC[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C

Procedure:
5.22 g (16.0 mmol) 3-(2-Amino-phenoxy)-2-tert-butoxycarbonylamino-pentanoic acid and 3.12 g (15.9 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride in 71 ml dimethylformamide were stirred overnight at room temperature. Extraction with saturated aqueous sodium hydrogencarbonate/ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:2 followed by chromatography on Chiralpak AD with heptane/ethanol 80:20 yielded 0.46 g (−)-((6R,7S)-6-ethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester, [1H-NMR (ppm, CDCl3): 1.11(t, 3H), 1.42 (s, 9H), 1.5–1.9 (m, 2H), 4.53–4.62 (m, 1H), 4.76 (mc, 1H), 5.57 (d, 1H), 6.94–6.97 (m, 1H), 7.0–7.1 (m, 1H), 7.1–7.18 (m, 2H), 8.08 (broad, 1H)], and 590 mg (+)-((6S,7R)-6-ethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester, [1H-NMR (ppm, CDCl3): 1.11(t, 3H), 1.42 (s, 9H), 1.5–1.9 (m, 2H), 4.53–4.62 (m, 1H), 4.76 (mc, 1H), 5.57 (d, 1H), 6.94–6.97 (m, 1H), 7.0–7.1 (m, 1H), 7.1–7.18 (m, 2H), 7.39 (broad, 1H)].
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:35]=1[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>O.ClCCl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][C:35]=1[CH2:46][N:47]1[CH2:52][CH2:51][N:50]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[CH2:49][CH2:48]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(-c2ccccc2)ccc1CN1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.9 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (63.0 mg, 0.210 mmol, 0.30 equiv), dichloromethane (20 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (119 mg, 0.710 mmol, 1.00 equiv). N,N-Diisopropylethylamine (174 mg, 1.35 mmol, 1.90 equiv) was added dropwise. The resulting solution was stirred for 2 h at room temperature. 1-[(2-Methoxy-4-phenylphenyl)methyl]piperazine (200 mg, 0.710 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (5 mL). The resulting mixture was extracted with dichloromethane (3×5 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (260 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 120 mg (36% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.60 (t, J=4.2 Hz, 2H), 7.32-7.46 (m, 4H), 7.15-7.18 (m, 1H), 7.60 (d, J=1.2 Hz, 1H), 5.72-5.80 (m, 1H), 3.88 (s, 3H), 3.58-3.63 (m, 6H), 2.51-2.57 (m, 4H). LCMS: (ESI, m/z): 477 [M+H]+.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@H:8]([C:10]1[N:11]([CH3:29])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:9])(C)C.[CH3:42][C:43](=[CH2:45])[CH3:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>ClCCl>[C:43]([O:9][C@@H:8]([C:10]1[N:11]([CH3:29])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][OH:6])([CH3:45])([CH3:44])[CH3:42]
Reactant: C=C(C)C
Reactant: Cc1ccc(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2c([C@@H](CO)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
A −78° C. suspension of 3-((1S)-2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1-hydroxyethyl)-4-(3,4-dimethylphenyl)-2-methyl-1(2H)-isoquinolinone (12 mg, 0.021 mmol) and amberlyst 15 resin (6 mg, 0.036 mmol) in Dichloromethane (DCM) (290 μl) was treated with isobutylene until the volume approximately doubled. The reaction mixture was sealed and allowed to warm to ambient temperature. After 48 h, the reaction mixture was cooled to −78° C. and then opened to the atmosphere. The reaction mixture was filtered through a short pad of silica and rinsed with EtOAc. The filtrate was concentrated in vacuo. The residue was dissolved in Tetrahydrofuran (THF) (290 μl) and treated with 1.0 M TBAF in THF (145 μl, 0.145 mmol). After 2 h, the reaction mixture was filtered through a short pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo and purified by reverse phase hplc to afford the title compound (6 mg, 0.016 mmol, 43.6% yield) as a white solid: Rt=1.02, ES+ MS: 380 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8]O)[CH2:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:11][CH2:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCC1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCC1CCOC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
3-(Tetrahydro-3-furanyl)-1-propanol (1 g, 7.68 mmol) was dissolved in DMF (10 ml) and carbon tetrabromide (5.09 g, 15.36 mmol) added. The solution turned yellow. The solution was cooled to 0° C. and triphenylphosphine (4.03 g, 15.36 mmol) added dropwise as a solution in DMF (20 ml) (˜30 mins, temperature maintained <2° C. throughout). The reaction mixture was stirred at 0° C. for 1 hour before gradually allowing to warm to room temperature and stirred for a further 2 hours. The solvent was removed in vacuo. Attempted trituration of the resultant brown oil with either DCM or cyclohexane was unsuccessful. The solvent was removed and the oil diluted with DCM and was purified by chromatography on silica (100 g) using a 0-25% ethyl acetate-cyclohexane over 40 mins using a Flashmaster II. The appropriate fractions were combined and dried down to give the title compound as a yellow oil (0.676 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)C.CO>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a stirring solution of 4-hydroxybenzylamine (0.5 g, 4.06 mmol) and TEA (2.26 mL, 16.24 mmol) in DCM (20 mL) at 0° C. was added 4-nitrobenzoyl chloride (1.66 g, 8.93 mmol) and left at room temperature for 1 h. The reaction mixture was diluted with DCM (100 mL), washed with NaHCO3 (50 mL), and the organic layer reduced to dryness. The resulting residue was diluted with MeOH (25 mL) and DCM (5 mL), to which NaOH (18.0 mL, 1.0 M) was added. After stirring at room temperature for 10 min, analysis showed the bis-acylated material was cleaved to give the desired mono-acylated product. The reaction mixture was acidified with acetic acid until neutral and the MeOH removed under vacuum. The product was extracted into DCM (50 mL) and washed with brine (50 mL). The organic residue was purified by chromatography (EA/hexanes), to afford 647 mg (58%) of N-(4-hydroxybenzyl)-4-nitrobenzamide INT-1. LCMS-ESI (m/z) calculated for C14H12N2O4: 272; found 273 [M+H]+, tR=1.84 min (Method 5).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[N:5]2[CH2:4]1.[CH3:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:38][C@H:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:30])[N:12]=3)[N:5]2[CH2:4]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CN(C)C1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(N(C)C)C3)n1)c1ccccc1
Temperature: 140 °C

Procedure:
A solution of the crude 6-dimethylamino-2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1one, 25, prepared as described herein above (4.2 g, 10 mmol) and (S)-(−)-α-methyl-benzyl amine (45.2 mL, 351 mmol) are dissolved in toluene (100 mL). The resulting mixture is heated to 140° C. for 12 hours, cooled to room temperature and the solvent removed in vacuo. The resulting residue is purified over silica (1:1 EtOAc/hexanes) to afford the desired product.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][OH:18]>CO>[OH:18][N:17]=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)c2ccccc12
Solvent: CO
Product: COC(=O)c1ccc(C=NO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-formyl-1-naphthalenecarboxylate (2.2 g, 10.3 mmol) in methanol (50 mL) was added a solution of hydroxylamine (1.33 mL, 50% in water). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (2.55 g).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:67][CH2:66][CH:65]([N:68](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C:69]([NH2:71])=[NH:70])[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[NH:68]([CH:65]1[CH2:66][CH2:67][N:62]([C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:63][CH2:64]1)[C:69]([NH2:71])=[NH:70]
Reactant: N=C(N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCC(NC(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl -1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonylguanidino)piperidin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 5) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17]I>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][C:12]1=[O:16]
Reactant: CI
Reactant: O=C1CN(Cc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC1=O

Procedure:
Sodium hydride (50% in oil, 10.4 g., 0.22 mole) is added to a stirred solution of 4-(phenylmethyl)piperazinone (Example 45, 38.0 g., 0.20 mole) in THF (2.0 l.). After 1 hour mehyl iodide (80.0 g., 0.75 mole) is added and the reaction solution is refluxed for 2.5 hours. The THF is removed under reduced pressure and the residual oil is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is chromatographed on silica gel to give the title compound, which is converted to the p-TSA salt, m.p. 138°-140°.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(-c2cccc(N)c2)cn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 84% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:14]3[CH2:13]2)=[CH:4][CH:3]=1.[S:22](Cl)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:13]1[N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:22](=[O:25])(=[O:24])[NH2:23])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:14]12
Reactant: NS(=O)(=O)Cl
Reactant: Oc1ccc2ccnc(N3CCN4CCCCC4C3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1ccc2ccnc(N3CCN4CCCCC4C3)c2c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
In 3 ml of N-methylpyrrolidone, 105 mg of 7-hydroxy-1-octahydropyrido[1,2-a]pyrazin-2-ylisoquinoline as synthesized in Production Example 84 was dissolved, and to the solution 1.00 g of sulfamoyl chloride was added, followed by an hour's stirring at room temperature. The solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (25% aqueous ammonia:methanol:chloroform=1:10:90) to provide 85 mg (75%) of 1-octahydropyrido[1,2-a]pyrazin-2-yl-7-sulfamoylisoquinoline.