Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([OH:39])=O)=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:96]([OH:98])=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]([O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:90])=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:96]([OH:98])=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]([O:91][C:92]([CH3:94])([CH3:95])[CH3:93])=[O:90])=[O:81])=[O:39])=[CH:33][CH:32]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (15.1 mg, 0.021 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (7 μl, 0.064 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (10.8 mg, 0.034 mmol) was added and the reaction mixture was stirred at the same conditions for 1 hour. Glycyl-N6-(tert-butoxycarbonyl)-D-lysine (10.0 mg 0.033 mmol) was added and the reaction mixture was stirred for 2 hours. The mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in a 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. M/z: 996.74 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=4)[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:14]=3[C:13](=[O:15])[C:12]=2[CH:11]=1
Reactant: Cn1ncc2[nH]c3ccc(Cc4cccc([N+](=O)[O-])c4)cc3c(=O)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(N)c4)cc3c(=O)c21
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of 1-methyl-7-(3-nitrobenzyl)-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 23, step 2, 76 mg, 0.23 mmol), iron powder (63 mg, 1.1 mmol), and ammonium chloride (12 mg, 0.023 mmol) in ethanol (15 ml) and water (5 ml) was refluxed for 2 h. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was collected by filtration and washed with ethanol and diisopropyl ether to give 60 mg (88%) of 7-(3-aminobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one. 24 mg of this solid was treated with methanolic hydrochloric acid and the mixture was evaporated. The residue was washed with diisopropyl ether to give 29 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[C-]#[N:13].[K+].C[CH:16]([OH:18])C.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:16](=[O:18])[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CO)c1cccc(Cl)c1
Reactant: [C-]#N
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(Cl)c2)co1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a mixed solution of 1-(3-chlorophenyl)-2-hydroxyethanone (21.8 g), potassium cyanide (20.8 g) and 2-propanol (100 mL) was added acetic acid (18 mL) at room temperature. After stirring for 30 min, water was added, and the precipitated crystals were collected by filtration and recrystallized from methanol-diisopropyl ether to give 4-(3-chlorophenyl)oxazol-2(3H)-one (6.7 g, yield 41%) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[C:57]([Cl:59])[CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][CH:48]=1)[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:59][C:57]1[CH:56]=[CH:55][C:54]([F:60])=[C:53]([C:50]2[CH:49]=[CH:48][C:47]([CH2:46][C@@H:37]([NH:36][C:9]([C:7]3[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:8]=3)=[O:11])[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41])=[CH:52][CH:51]=2)[CH:58]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CCCc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.8 %

Procedure:
3-Propylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C26H28ClFN2O5, 503.17. found 504.2.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH2:3]1.C[Mg]Br>O1CCCC1.C(OCC)C>[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([NH2:1])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1)([CH3:12])([CH3:9])[CH3:11]
Reactant: CC(C)(C#N)N1CCCC(N)(c2ccccc2)C1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)N1CCCC(N)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
To a solution of 100 mg (0.411 mmol) rac-2-(3-Amino-3-phenyl-piperidin-1-yl)-2-methyl-propionitrile in 2.0 ml tetrahydrofuran over mol-sieve at 0° C. under nitrogen, was added dropwise 1.4 ul (4.11 mmol) of a 3M methylmagnesium bromide solution in diethyl ether. The mixture was stirred at 0° C. for 10 minutes, and then at 60° C. for 30 hours. The mixture was cooled in an ice bath and quenched with a saturated ammonium chloride solution. The mixture was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 60 mg (63%) of the title compound as a yellow gum. MS (m/e): 233.2 (M+H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[S:26]([C:29]1[CH:34]=[CH:33][C:32](Cl)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(=O)([O-])[O-:39].[K+].[K+].O>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:22]=[CH:23][C:11]([S:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[O:39][C:32]2[CH:33]=[CH:34][C:29]([S:26]([C:25]([F:37])([F:36])[F:24])(=[O:28])=[O:27])=[CH:30][CH:31]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(S(=O)(=O)c2ccccc2Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of ethyl [4-(4-hydroxyphenylsulfonyl)phenoxy]acetate (100 mg, 0.3 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (73 mg, 1 equiv.) and potassium carbonate (164 mg, 4 equiv.) in DMF was heated to 100° C. overnight. The reaction was poured into water, extracted with EtOAc, washed with organic layer with water, brine, dried and concentrated. The residue was column chromatographed to give{4-[4-(4-trifluoromethanesulfonyl-phenoxy)-benzenesulfonyl]-phenoxy}-acetic acid ethyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.11 (d, J=8.92 Hz, 2H), 8.03 (d, J=8.77 Hz, 2H), 7.90 (d, J=8.98 Hz, 2H), 7.39-7.43 (m, 4H), 7.14 (d, J=8.77 Hz, 2H), 4.90 (s, 2H, CH2), 4.15 (q, J=7.02 Hz, 2H, OCH2CH3), 1.19 (t, J=7.02 Hz, 3H, OCH2CH3). MS-EI m/z 544 [M+].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[CH:9]12[O:8][CH:12]([CH:11]=[CH:10]1)[CH:3]1[CH:2]2[C:1](=[O:7])[O:6][C:4]1=[O:5]
Reactant: c1ccoc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(O3)C12
Temperature: 80 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
Maleic anhydride (30.00 g, 0.306 mol) was suspended in 150 mL of toluene and the mixture warmed to 80° C. Furan (33.4 mL, 0.459 mol) was added via syringe and the turbid solution stirred for 6 h. The mixture was then cooled to room temperature and the stirring was stopped. After 1 h the resulting white crystals were filtered off and the solid washed with 2×30 mL of petroleum ether. Obtained 44.40 g (0.267 mol, 87% yield) of the desired product as small white needless. m.p. 124-127° C. (dec.) IR (neat): 1857, 1780, 1309, 1282, 1211, 1145, 1083, 1019, 947, 920, 902, 877, 847, 800, 732, 690, 674, 633, 575 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=3.17 (s, 2H, CH), 5.45 (t, J=1.0 Hz, 2H, CHO); 6.57 (t, J=1.0 Hz, 2H, CHvinyl). 13C{1H}NMR (100.59 MHz, CDCl3, 298 K) δ=48.85 (2C, CH), 82.35 (2H, CHO), 137.12 (2C, CHvinyl) 170.04 (2C, CO). Anal. Calcd. for C8H6O4: C, 57.84; H, 3.64. Found C, 57.74; H, 3.68.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[NH:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:3]2[C@H:4]([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C@@H:2]2[CH3:1])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
The crude cis-2,6-dimethylpiperidin-4-one 91 from previous experiment (1.1 g, 8.6 mmol) was dissolved in CH2Cl2 (50 mL) and triethylamine (5 mL, 35 mmol) was added. Stirred solution was treated with 4-chlorobenzenesulfonyl chloride (2.2 g, 9.5 mmol). The mixture was stirred for 24 hr then was divided between water (100 mL) and CH2Cl2 (100 mL). Organic layer was washed with 0.2 N citric acid, water, brine and dried over anhydrous Na2SO4. The solution was filtered and evaporated. The residue was purified by flash chromatography, eluting with EtOAc-hexane (1:3) mixture. Yield 60 mg (2% after two steps).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].C(=O)([O-])[O-].[Cs+].[Cs+].[N:18]([CH2:21][CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)[CH:26]=[CH:27][CH:28]=1)=[C:19]=[O:20]>C(#N)C.ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:19]([NH:18][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:36][CH:35]=3)[N:30]=2)[CH:24]=1)=[O:20])=[S:9]
Reactant: Cc1ccccc1NC(N)=S
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a 20 mL vial, 1-(o-tolyl)thiourea (0.096 g, 0.58 mmol) and cesium carbonate (0.22 g, 0.68 mmol) were charged as solids. Then 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) (0.20 g, 0.52 mmol) in acetonitrile (4.0 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane and filtered through a phase separator. The filtrate was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by flash column chromatography using 10-50% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent to provide the title compound as a white solid (0.11 g, 37%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.12 (s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.66-7.54 (m, 3H), 7.54-7.46 (m, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.14 (m, 2H), 7.03 (t, J=5.6 Hz, 1H), 3.46 (q, J=6.6 Hz, 2H), 2.96-2.84 (m, 2H), 2.20 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 541 ([M+H]+), 539 ([M−H]−).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([OH:37])(=[S:36])[CH3:35].[CH3:38][C@:39]12[CH2:56][CH2:55][C@H:54]3[C@@H:44]([CH2:45][C@H:46]([OH:58])[CH:47]4[C@:52]3([CH3:53])[CH2:51][CH2:50][C@H:49](O)[CH2:48]4)[C@@H:43]1[CH2:42][CH2:41][C@@H:40]2[OH:59]>C1COCC1.CCOC(C)=O>[C:34]([S:36][C@@H:49]1[CH2:50][CH2:51][C@@:52]2([CH3:53])[CH:47]([C@@H:46]([OH:58])[CH2:45][C@@H:44]3[C@@H:54]2[CH2:55][CH2:56][C@@:39]2([CH3:38])[C@H:43]3[CH2:42][CH2:41][C@@H:40]2[OH:59])[CH2:48]1)(=[O:37])[CH3:35]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of triphenylphosphine (2.38 g) in THF (140 mL) cooled at 0° C., diisopropyl azodicarboxylate (1.79 mL) was added dropwise. After stirring for 30 minutes, thioacetic acid (0.65 mL) and androstane-3β,6α,17β-triol (2.00 g) were added. After 2 hrs at 0° C. and overnight at room temperature EtOAc was added. The mixture was washed with water and the organic layer evaporated to dryness. The crude product was purified by flash chromatography (SiO2, cyclohexane:EtOAc 55:45) to give 3α-acetylthioandrostane-6α,17β-diol (1.60 g, 66%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.42 (1H, bb), 4.28 (1H, bb), 3.91 (1H, bb), 3.42 (1H, m), 3.11 (1H, m), 2.28 (3H, s), 2.00-0.80 (20H, m), 0.74 (3H, s), 0.60 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:4]>C(Cl)Cl.C(O)(=O)C.[Zn]>[C:3]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])(=[O:4])[CH3:2]
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 433 mg of benzyl α-(3ξ-chloroacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 4 ml of methylene chloride and 4 ml of acetic acid is added 450 mg of zinc powder, and the mixture stirred at room temperature for 1 hour. The reaction mixture is filtrated and the filtrate diluted with water and extracted with methylene chloride. The extract is washed with water, dried and evaporated to yield 375 mg of benzyl α-(3ξ-acetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as an oily material in 98% yield.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-:12].[Na+].[CH3:14][O:15][C:16]1[CH:34]=[CH:33][C:19]2[C:20](=O)[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)O[C:18]=2[CH:17]=1>CO.C(Cl)(Cl)Cl>[OH:12][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]1[N:10]=[C:20]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:34][CH:33]=2)[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[N:9]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2nc(=O)c3ccc(OC)cc3o2)cc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccccc3O)n2)cc1

Procedure:
4.9 g (10.86 mmol) of benzamidine hydrochloride (38% in methanol) and then a solution of 1.95 g (10.86 mmol) of sodium methoxide (30% in methanol) are added to a suspension of 2.83 g (10 mmol) of 7-methoxy-2-(4-methoxyphenyl)-4H-1,3-benzoxazin-4-one in 48 ml of methanol. The mixture is heated to boiling and diluted with 38 ml of methanol. After refluxing (30 minutes), the precipitate is filtered off with suction while hot and washed twice with 10 ml of methanol each time. Recrystallization from chloroform/petroleum ether gives 3.74 g (97% of theory) of the product of the formula ##STR25## M.p.: 171°-172° C. UV spectrum (2.25·10-5 mol in chloroform) λmax /εmax =297/34920 325/shoulder
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40]([NH2:42])=O)[S:39][C:31]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40](=[S:10])[NH2:42])[S:39][C:31]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Yield: 38.8 %

Procedure:
To a mixture of Lawesson's reagent (26.3 mg, 0.065 mmol) and the compound of Example 127 (50 mg, 0.13 mmol) was added toluene (10 mL) and the reaction heated at 110° for 1 h. A further portion of Lawesson's reagent (52.6 mg, 0.13 mmol) was added and reaction heated for 6.5 h. The reaction was diluted with DCM, washed with water, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 5–10% EtOAc in DCM) to give the title compound as a yellow solid (10 mg, 20%). δH (MeOH-d4) 7.67 (1H, m), 7.58–7.46 (7H, m), 7.40 (3H, m), 6.48 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.41 minutes, 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:12][C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[N:14]=2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=3)[N:14]=2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(-n2nc(C=C(C(=O)O)c3cccc(Cl)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(-n2nc(CC(C(=O)O)c3cccc(Cl)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 100 °C
Yield: 23.1 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylic acid (Example 108, Step B; 0.043 g, 0.084 mmol) in EtOH (5 mL) was added tosylhydrazine (0.22 g, 1.2 mmol). To the light yellow solution was added a mixture of NaOAc (0.098 g, 1.2 mmol) in H2O (1 mL). The resulting mixture was heated to 100° C. overnight, then cooled to rt, diluted with H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (MgSO4) and then concentrated to provide a yellow oil. The oil was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the pure alkane as a colorless oil (10 mg, 23%). TLC (silica gel, 9:1 CH2Cl2/MeOH): Rf=0.43. HPLC: Rt=10.7 (Method A). MS (ESI): mass calculated for C26H21Cl3N2O3, 514.06; m/z found, 513 [M−H]−. 1H NMR (400 mHz, CDCl3): 7.32-7.23 (m, 6H), 7.14-7.10 (m, 2H), 6.92-6.89 (m, 1H), 6.88-6.85 (m, 2H), 6.23 (s, 1H), 4.03 (q, J=6.9 Hz, 2H), 4.04-4.00 (m, 1H), 3.50 (dd, J=6.7, 14.7 Hz, 1H), 3.09 (dd, J=8.7, 14.7 Hz, 1H), (1.42 (t, J=7.0 Hz, 3H),
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:16]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 70 °C

Procedure:
To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI, and the mixture heated at 70° C. for 1 h. 770 mmol methanol was then added and the mixture was heated at 70° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant:ethyl acetate/heptane/dichloromethane 45:45:10) to afford the title compound. MS (m/e): 244.1 ([M−H]−, 100%)