Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:16]=[C:17]([C:24]2[S:28][C:27]([CH2:29][CH2:30][C@@H:31]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:32][C:33]3[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=3)=[N:26][N:25]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>C1COCC1>[C:46]([O:45][C:44]([NH:43][C@@H:31]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=1)[CH2:30][CH2:29][C:27]1[S:28][C:24]([C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:16]=2)=[N:25][N:26]=1)=[O:50])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)Cc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (48 mg, 1263 μmol) was added to a solution of diethyl malonate (191 μL, 1263 μmol) in THF (2 mL) and the mixture was stirred at room temperature for 15 minutes. This mixture was added to a solution of tert-butyl (R)-4-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (171 mg, 316 μmol) in THF (3 mL) and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned between saturated aqueous NH4Cl (15 mL) and DCM (15 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 40% to 70% EtOAc/hexanes) to provide diethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (204 mg, 95% yield) as a yellow solid. LCMS (API-ES) m/z: 703.6 (M+Na+).
Reaction SMILES: [OH2:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([OH:9])[CH3:8].ClCl>O1CCCC1>[CH3:8][C:7]1[O:9][CH:6]=[CH:5][C:4](=[O:1])[C:3]=1[OH:2]
Reactant: O
Reactant: CC(O)c1ccco1
Agent: ClCl
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The solution was cooled to a temperature of 0° to 10° C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.089 moles) in 20 ml of tetrahydrofuran and this was added dropwise to the stirred reaction flask while chlorine (0.30 mole) was added via the gas inlet tube. The rate of addition was such that all the alcohol was added in the first 1.3-1.5 equivalents of chlorine (approximately 30 minutes) while maintaining the reaction temperature below 10° C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation. When the reaction mixture reached a temperature of about 105° C., a condenser was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2.2 and the reaction mixture was cooled to 5° C. Crystallization and filtration yielded 3.43 grams of crude 3-hydroxy-2-methyl-γ-pyrone (maltol). The aqueous filtrate was extracted with CHCl3 to obtain a second crop of 2.58 g of maltol. Distillation of the combined solids and recrystallization from methanol gave 5.5 g (49%) of pure white maltol, m.p. 159.5°-160.5° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:3][C:4]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([C:25]4[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:9][CH:10]=3)[N:5]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: FC(F)(F)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Reactant: C1CCNC1
Agent: Cl
Product: FC(F)(F)c1ccc(Nc2nc(CN3CCCC3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a solution of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine HCl (30 mg, 0.058 mmol) in pyrrolidine (1 mL) at 100° C. for 1 hour. Remove the excess pyrrolidine under reduced pressure and partition the residue between EtOAc and 10% NaOH solution. Dry the EtOAc layer (Na2SO4) and concentrate under reduced pressure to give [2-Pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam. Mass Spec 517.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([CH2:24][C:25](OCC)=[O:26])(=O)[C:19]([CH3:22])([CH3:21])[CH3:20]>O>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:25]([OH:26])=[CH:24][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Solvent: O
Product: CSc1nn2c(O)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Yield: 48 %

Procedure:
2 g (7.4 mmol) of 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 2.91 ml (18.3 mmol) of ethyl pivaloylacetate were added to 27 g of polyphosphoric acid and heated to 120° for 5 hrs. After cooling 100 ml of water were slowly added thereto and the mixture was extracted three times with CH2Cl2. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/EtOAc) yielded 1.34 g (48%) of 3-benzenesulphonyl-5-tert-butyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>[Pd]>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccnc1Cl
Agent: [Pd]
Product: COC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared by palladium [PdCl2 (dppf)] catalyzed coupling of 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give an oil: 1H NMR (CDCl3, 300 MHz): δ 8.80 (1H dd), 8.19 (1H, dd), 7.67 (4H, q), 7.40 (1H, dd), 3.70 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3ccccc3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanone (55 mg) (compound 220) was dissolved in methanol (3 ml) to prepare a solution. Sodium borohydride (26 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (52 mg, yield 92%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% in oil, 19.41 mg, 0.485 mmol) was added to a solution of (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 100 mg, 0.441 mmol) in DMF (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, after which tert-butyl bromoacetate (0.078 mL, 0.529 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20-80% EtOAc/hexane gradient) to afford the title compound as an off-white solid (101 mg, 67.2%). 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (m, 9H), 3.01-3.11 (m, 1H), 3.15-3.29 (m, 2H), 3.37 (dd, J=11.37, 8.84 Hz, 1H), 3.58 (td, J=11.94, 2.91 Hz, 1H), 3.64-3.76 (m, 2H), 3.88-4.07 (m, 3H), 4.53 (dd, J=13.89, 2.02 Hz, 1H), 7.22 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O3, 341.13. found 341.2
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][N:5]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:6]=1
Reactant: N#Cc1[nH]ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C#N)n2)CC1
Yield: 60.7 %

Procedure:
4-bromo-2H-pyrazole-3-carbonitrile (500 mg), potassium carbonate (522 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (975 mg) in acetonitrile (15 ml) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethylacetate, washed with water and brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford. tert-butyl 4-(4-bromo-3-cyano-pyrazol-1-yl)piperidine-1-carboxylate (627 mg) The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.74 (dd, 1H), 1.78 (dd, 1H), 1.98-2.08 (m, 2H), 2.90 (bs, 2H), 3.95-4.11 (m, 2H), 4.46-4.57 (m, 1H), 8.45 (s, 1H).
Reaction SMILES: [Br:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[I:28])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:3](=[O:4])[C:2]([Br:1])([F:7])[F:6])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[I:28])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2I)CC1
Reactant: O=C(Cl)C(F)(F)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)C(F)(F)Br)c2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Bromodifluoroacetyl chloride (0.800 g, 4.1 mmol) was added dropwise to a cooled (0° C.) solution of 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.500 g, 3.7 mmol) and triethylamine (1.0 mL, 7.1 mmol) in dichloromethane (20 mL). The cooling bath was removed 30 minutes after the addition of all reagents. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Purification of the residue by flash chromatography to afford 4-[(2-bromo-2,2-difluoroacetyl)-(2-iodophenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.730 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=1.2 and 7.8 Hz, 1H), 7.41-7.06 (m, 3H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 2H), 2.81-2.64 (m, 2H), 2.18-2.12 (m, 1H), 1.89-1.84 (m, 1H), 1.59-1.52 (m, 1H), 1.40 (s, 9H), 1.25-0.98 (m, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(C)(C)C.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25]>C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O

Procedure:
Accordingly, the present invention also includes a process for the manufacture of these compounds. Such a process embraces in a first step the manufacture of a mixed anhydride and its conversion into quinargine as described above. The mixed anhydride, e.g. 2,2-dimethylpropionic acid-quinoline-2-carboxylic acid anhydride, can be obtained by adding an adjuvant base, e.g. triethylamine, to a mixture of quinoline-2-carboxylic acid and a reactive acid derivative, preferably pivaloyl chloride. The resulting mixed anhydride is subsequently reacted with asparagine in alkaline solution to give N-(2-quinolylcarbonyl)-L-asparagine. This substance is then converted in a subsequent step with 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide into N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]-amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as described above or optionally into a corresponding salt, preferably the methanesulphonic acid salt, or into an ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13]1([CH2:16][CH2:17]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:13]1([CH2:16][CH2:17][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: OCCC1CC1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCCC3CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (1.0 g, 6.0 mmol), 2-cyclopropylethanol (640 mg, 7.0 mmol) and triphenylphosphine (3.25 g, 12 mmol) in THF (100 mL) was added DEAD (2.13 g, 12 mmol) at 0° C. The reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=12:1) to give 470 mg (33%) of the title compound as a red oil. 1H NMR (300 MHz, CDCl3): δ 0.13-0.15 (2H, m), 0.50-0.52 (2H, m), 0.86-0.93 (1H, m), 1.68-1.74 (2H, m), 2.11-2.15 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.93 (2H, t, J=6.0 Hz), 4.10 (2H, t, J=6.6 Hz), 6.73 (1H, s), 6.83 (1H, dd, J=2.4, 8.7 Hz), 8.02 (1H, d, J=8.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([NH2:28])(=[O:27])=[O:26])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].C(O)(=O)C>CO>[NH2:28][S:25]([NH:24][CH2:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:26])=[O:27]
Reactant: NS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A solution of N-[3-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)propyl]sulfamide (35 mg, 73 μmol) in methanol (1 mL) was treated with 2 M NaOH (0.3 mL, 0.6 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered, and purified by preparative LCMS to give the desired product (14 mg, 42%) as a solid. LCMS for C12H16BrFN7O4S (M+H)+: m/z=451.8, 453.9, 1H NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 8.89 (s, 1H), 7.17 (dd, J=8.8, 8.6 Hz, 1H), 7.09 (dd, J=6.1, 2.7 Hz, 1H), 6.76-6.72 (m, 1H), 6.56 (dd, J=6.1, 6.1 Hz, 1H), 6.51 (s, 2H), 6.17 (dd, J=5.9, 5.9 Hz, 1H), 3.27-3.21 (m, 2H), 2.94-2.88 (m, 2H), 1.78-1.71 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@H:4](/[CH:5]=[C:6](\[CH3:13])/[CH:7]=[N:8][O:9][CH2:10][C:11]#[CH:12])[C@H:3]1[C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C@H:4](/[CH:5]=[C:6](\[CH3:13])/[CH:7]=[N:8][O:9][CH2:10][C:11]#[CH:12])[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.2 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.46 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylate, catalytic amount of p-toluenesulfonic acid and 10 ml of toluene was stirred for 3.5 hours under reflux. The reaction mixture was cooled down to room temperature, then, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylic acid:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11].C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>CCCCCC.C(OCC)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:17]([OH:19])=[O:18])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: O=C=O
Reactant: Cc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The product of step (a) above (4.3 g) was mixed with diethyl ether (30 ml), the mixture cooled to -70° C., and maintained at this temperature whilst a solution of n-butyllithium in n-hexane (1.6 M, 16.4 ml) was slowly added. The mixture was stirred for a period of 1 hour during which time a fine white precipitate was formed. Dry carbon dioxide gas was then passed into the mixture for 30 minutes whilst the temperature was maintained within the range -70° to -40° C., and continued to be passed in thereafter whilst the mixture was allowed to warm to the ambient temperature. After acidifying with dilute hydrochloric acid (6 N, 40 ml) the organic phase was separated, washed with water and dried over anhydrous magnesium sulphate. After evaporation of the solvents under reduced pressure the residual solid was recrystallised from toluene to yield 2,3,5,6-tetrafluoro-4-toluic acid, m.p. 170° C. identified by infra red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([C:37](Cl)=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:32]3[S:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added thenoyl chloride (0.71 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.88 g, yield 64%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: C=CC(=O)OC
Reactant: Cc1cccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1
Solvent: CO
Solvent: COCCOC
Product: Cc1cccc(C=CCC(CCC(=O)O)(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1
Reaction time: 96 h

Procedure:
Triton B (2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4-phenyl-7-(m-methylphenyl)-1,6-heptadien-3-one (19.33 g., 0.05 mole) in glyme (250 ml.) followed by the addition of methyl acrylate (4.73 g., 0.055 mole) in glyme (50 ml.). The solution is stirred for 96 hours and the solvent is removed under reduced pressure. The residue is suspended in methanol (700 ml.) and a 20% sodium hydroxide solution (35 ml.) is added. After an additional 24 hours, the methanol is evaporated in vacuo and the residue is dissolved in water. Extraction with ether removes unreacted ketone. The aqueous solution is acidified and the solid that separates is collected, washed well with water, and air-dried, yield 9.78 g., m.p. 135°-144°C. Recyrstallization from butyl chloride produces material with m.p. 154°-155°C.