Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[O:49][N:48]=[C:47]([CH2:50]O)[CH:46]=2)=[CH:41][CH:40]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:22]([CH3:24])[CH3:23].C(Br)(Br)(Br)[Br:53].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:53][CH2:50][C:47]1[CH:46]=[C:45]([C:42]2[CH:43]=[CH:44][C:39]([C:21]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:27][N:26]=3)([CH3:20])[CH:22]([CH3:24])[CH3:23])=[CH:40][CH:41]=2)[O:49][N:48]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)C(C)(c1ccc(-c2cc(CO)no2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(-c2cc(CBr)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1.5 h

Procedure:
Triphenylphosphine (1.34 g, 5.21 mmol) was added to a stirred solution of 1d (1.49 g, 3.47 mmol) and carbon tetrabromide (1.73 g, 5.21 mmol) in THF (100 mL) at rt. After approximately 1.5 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were dried (magnesium sulfate), concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-70% EtOAc/hexanes as eluent) to afford the title compound 1e. m/z (ES) 494 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C)=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[ClH:32].[K+].[Br-]>C(Cl)(Cl)Cl.CO>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2OCc2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2oc3ccc(N)cc3c(=O)c2OCc2ccccc2)cc1
Yield: 54 %

Procedure:
Prepared analogously to Example 5c) starting from 2-(4-methoxyphenyl)-3-benzyloxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 54%; TLC (9/1 Chloroform/Methanol) Rf: 0.60; Elem. anal. C23H19NO4*HCl; theory C, 67.40; H, 4.92; N, 3.42. found C, 64.24; H, 4.73; N, 3.20. IR (KBr): 3433, 2833, 2592, 1629, 1498, 1167 cm−1, 1H-NMR (d6-DMSO): 8.0 (m, 2H), 7.73 (m, 2H), 7.52 (dd, 1H), 7.37-7.22 (m, 5H), 7.10 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10](Br)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]([C:27]3[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=3)=[CH:9][C:5]3[O:6][CH2:7][O:8][C:4]=3[CH:3]=2)=[CH:15][CH:14]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1cc2c(cc1Br)OCO2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 142.6 %

Procedure:
Under nitrogen, 1 g of Pd(PPh3)4 was added to a stirred solution of 4 g (14.3 mmol) of 5,6-dibromo-1,3-benzodioxole (Lancaster), 2.4 g (17.2 mmol) of 4-fluorophenyl boronic acid, and 2.87 g (17.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) in 70 mL of toluene, 40 mL of ethanol, and 30 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried over Na2 SO4. Concentration in vacuo gave 6.9 g of 5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-1,3-benzodioxole as a semi-solid which was used without further purification.
Reaction SMILES: ClC(=C)CO[C:5]1[CH:14]=[C:13]2[C:8]([C:9](C)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.[C:18]([O:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])(=O)[CH2:19][CH2:20][CH3:21].C(Cl)(Cl)[Cl:30]>C(C1C=CC(C(C)C)=CC=1)(C)C>[Cl:30][C:6](=[CH2:7])[CH2:5][C:14]1[C:13]([O:12][C:11](=[O:15])[CH2:10][CH2:9][CH3:8])=[CH:21][CH:20]=[C:19]2[C:18]=1[O:23][C:24](=[O:28])[CH:25]=[C:26]2[CH3:27]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1
Reactant: ClC(Cl)Cl
Agent: CC(C)c1ccc(C(C)C)cc1
Product: C=C(Cl)Cc1c(OC(=O)CCC)ccc2c(C)cc(=O)oc12

Procedure:
Rearrangement of CAMC was accomplished in high yield by refluxing the allyl ether from Step 2 (143.5 gm; 0.55 mole) in a mixture of p-diisopropylbenzene (Aldrich, 1000 ml) and butyric anhydride (96 ml, 92.8 gm; 0.59 mol, Aldrich) under argon for 18 hours. The cooled reaction mixture was diluted with chloroform, washed with water and then saturated sodium bicarbonate, dried (MgSO4) then evaporated under reduced pressure. Following recrystallization from ethanol, 79.9 grams of mixed 6 and 8-(β-chloroallyl)-7-butyroxy-4-methylcoumarin (BCAMC,15) were obtained. HPLC analysis (Beckman; C18-ODS reverse phase column, isocratic elution with 60% CH3OH/40% H2O) showed the mixture to contain 85.7% of the desired 8-substituted isomer, of which a sample was purified by column chromatography (60-200 mesh silica gel, elution with CH2Cl2). The structures of the two isomers were confirmed by NMR. NMR (CDCl3) d 7.56 (1H, d), 7.11 (1H, d), 6.26 (1h, d), 5.05-5.19 (2H, m), 3.84 (2H, m), 2.55-2.62 (2H, m), 2.43 (3H, d), 1.78-1.82 (2H, m), 1 01-1 09 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH:3]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.[C:37]([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:11]=[CH:12][C:13]([CH3:37])=[CH:14][CH:15]=2)[CH3:9])=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Reactant: O=C([O-])O
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(Cl)ncc2N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 83.9 %

Procedure:
To the solution of 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine (18.87 g, 81.3 mmol) and DMAP (29.8 g, 243.9 mmol) in 200 mL of anhydrous toluene was added the solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (28.5 g, 89.4 mmol) in toluene under N2 atmosphere. The solution was heated at 120° C. for 23 hrs. Cooled to room temperature, poured into 1 L of 5% aq. NaHCO3 solution, and extracted with EtOAc twice. The combined organic phases were washed by water and brine consecutively, dried. over Na2SO4, filtered and purified by flash chromatography to afford 35 g 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide as a white solid (Yield: 83.9%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: N#CCc1ccc(F)cc1F
Reactant: COc1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(F)cc3F)c2N)cc1
Temperature: 0 °C
Yield: 54.3 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (1.000 g, 6.7046 mmol) and 2,4-difluoro phenyl acetonitrile (1.27 g, 8.0455 mmol) in absolute ethanol (20 ml), an ice-cooled solution of sodium methoxide (0.543 g, 10.0569 mmol) in absolute ethanol (10 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜2 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as brown solid (1.10 g, 48% yield). M.p. 152-156.5° C. LC-ESI-HRMS of [M+H]+ shows 303.1046 Da. Calc. 303.105742 Da, dev. −3.8 ppm.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=[O:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:31][C:16]12[CH2:28][CH2:27][C@:26]3([CH3:29])[CH:21]([CH:22]([CH3:30])[CH2:23][CH2:24][CH2:25]3)[C@@H:17]1[O:18][C:19](=[O:20])[CH:15]2[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CCC[C@]2(C)CCC3(O)C(CN4CCNCC4)C(=O)O[C@H]3C12

Procedure:
Compound of example 27 (100 mg, 0.47 mmol) was dissolved in methanol (10 mL) and 10% Pd(OH)2/C was added to it. The reaction mixture was hydrogenated (hydrogen pressure, 1 atm) for 30 hours. The reaction mixture was filtered over celite and concentrated to obtain the title compound
Reaction SMILES: [CH3:1]C1C=CC(C(NC2C(C)=CC=CC=2C)=N)=CC=1.[CH2:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]([NH:37][P:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:20][CH3:21].C([Li])CCC.CI>>[CH2:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]([N:37]([P:38]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:1])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccccc1N=C(NP(c1ccccc1)c1ccccc1)c1ccc(C)cc1
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Agent: [Li]CCCC
Solvent: CI
Product: CCCc1ccccc1N=C(c1ccc(C)cc1)N(C)P(c1ccccc1)c1ccccc1

Procedure:
Procedure as described for NSP Amidine III using the following amounts: 1.42 g of N′-(2-n-propylphenyl)-N-(diphenylphosphino)-4-methylbenzamidine (3.0 mmol), 1.50 mL of 2.0 M butyllithium (15.0 mmol), 1.50 mL of 2.0 M methyliodide (3.0 mmol). Following removal of lithium iodide via filtration and removal of solvent in vacuo, a yellow sticky residue was recovered (1.63 g, 67%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20]C=CC=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.[CH2:22](C1C=CC(C(C(OCC)=O)=O)=CC=1)C(C)C.C1C=CC([C@@H](N)CO)=CC=1.C(C1C=CC([C@@H](C)C(OC)=O)=CC=1)C(C)C>>[OH:13][C:9]1[C:10](=[O:12])[O:11][C@:7]([CH3:15])([C:4]2[CH:3]=[CH:2][C:1]([CH2:16][CH:21]([CH3:20])[CH3:22])=[CH:6][CH:5]=2)[C:8]=1[OH:14]
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Agent: COC(=O)[C@H](C)c1ccc(CC(C)C)cc1
Agent: N[C@@H](CO)c1ccccc1
Product: CC(C)Cc1ccc([C@@]2(C)OC(=O)C(O)=C2O)cc1
Yield: 15 %

Procedure:
(R)-(-)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (R)-(-)-Phenylglycinol was used to resolve the methyl (R)-(-)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g, (5 mmol) was converted into 190 mg (15% yield) of (R)-(-)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 180-181° C. dec. (CHCl3 /hexanes); [α]25D -137° (c=1.27; MeOH); 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4 : C, 68.68; H, 6.92. Found: C, 68.52; H, 7.01.
Reaction SMILES: [CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC(S(O[CH2:49][C@H:50]2[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]2)(=O)=O)=CC=1.O>CN(C=O)C>[CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:49][C@H:50]6[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: COc1cc(C2CN(C(=O)c3cc(O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2CN(C(=O)c3cc(OC[C@H]4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 47.4 %

Procedure:
To a suspension of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]-azetidin-1-yl}-(4-hydroxypyridin-2-yl)-methanone (0.45 g) prepared in a manner similar to Example (6) using 4-hydroxypyridine-2-calboxylic acid and K2CO3 (0.21 g) in DMF (8.0 mL) was added (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate (0.33 g). The reaction mixture was stirred at 100° C. for 13 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/2) to give the title compound (0.27 g, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1.O>CN(C)C=O>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:18][CH2:19]1
Reactant: CC1CCN(CCCCl)CC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(CCCSc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
Dissolve 8.50 g (55 mmol) of 4-nitrothiophenol in 40 mL of dimethylformamide and make basic with 13.7 mL of 4N potassium hydroxide. Add 10.60 g (60 mmol) of N-[3-chloropropyl]-4-methylpiperidine and heat this solution to 100° C. for 3 h. After this time cool the reaction to room temperature. Add 200 mL of water and extract with 2×150 mL of methylene chloride. Acidify the combined organic extracts to pH=1 with 1N hydrochloric acid and extract with 4×150 mL of water. Neutralize the combined aqueous extracts with saturated sodium bicarbonate solution and extract with 3×200 mL of methylene chloride. Dry the organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[O:7]=[CH:8][C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.[Cl-].[Na+].O>[O:7]1[CH2:3][CH:8]1[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CS(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A 100 mL flask was charged with NaH (116 mg, 2.9 mmol) and Me3S+OI− (639 mg, 2.9 mmol) under N2. Dry DMSO (6 mL) was added. The mixture was stirred at rt for 1 h. A second 100 mL flask was charged with (S)-tert-butyl 1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (500 mg, 1.9 mmol) dissolved in THF (5 mL) under N2. The solution of NaH and Me3S+OI− was added through a syringe. The resulting mixture was stirred for 1 h. at rt. Brine was added and the mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography to give tert-butyl (1S)-1-(oxiran-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (150 mg, 29%). 1H NMR (CD3OD) δ 1.45 (s, 9H), 2.60 (b, 1 h), 2.75 (m, 1H), 3.0 (b, 1H), 3.35 (m, 2H), 4.0 (m, 3H), 4.30 (b, 1H), 5.30 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:36][CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:36][CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[N:5][OH:6]
Reactant: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CCNC(=O)CN
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)CNC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 75 °C
Yield: 53 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde Oxime (i.e. the Product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (81 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-ethyl-acetamide (58 mg) and triethylamine (0.15 mL, 0.11 g) in THF (10 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (164 mg, 53%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])=[O:8]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: OCC1CCCCO1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Tetrahydro-2H-pyran-2-yl)methanol (0.51 g, 4.30 mmol) was dissolved in 10 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (3.04 g, 9.46 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.134 g, 0.86 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 hours, and the reaction was quenched by addition of 2×20 mL of 1 M NaOH. Basic solution was washed 3×30 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×30 mL of EtOAc, organic layers were combined, dried over sodium sulfate and evaporated. The title compound was isolated as an oil (0.34 g, 61%) was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ4.11 (d, 1H, J=10.5 Hz), 3.98 (d, 1H, J=9.9 Hz), 3.53 (m, 1H), 2.10-1.92 (m, 3H), 1.60-1.54 (m, 3H).
Reaction SMILES: [C:1]([O:6][C@H:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])[OH:19])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])(O)=O.[Na+:29]>O.C(#N)C>[Na+:29].[C:1]([O:6][CH:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[O-:20])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCP(=O)([O-])CCCNC(=O)OC(OC(=O)C(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
Compound 39 was dissolved in a mixture of water and acetonitrile, an aqueous solution of 1 eq. NaHCO3 was added, the mixture stirred for about 10 min, and lyophilized to afford the title compound (213). 1H-NMR (400 MHz, CDCl3): δ 6.55 (d, J=4.8 Hz, 1H), 3.10 (t, J=6.4 Hz, 2H), 2.53-2.56 (m, 1H), 1.97-2.00 (m, 1H), 1.79-1.83 (m, 2H), 1.70-1.74 (m, 2H), 1.53-1.58 (m, 2H), 1.37-1.43 (m, 2H), 1.15 (t, J=6.8 Hz, 6H), 0.90 (t, J=7.2 Hz, 9H).
Reaction SMILES: [C:1]1([CH:7]([NH2:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[C:18]#[CH:19].C(N(C(C)C)CC)(C)C>O1CCCC1>[ClH:15].[CH2:19]([NH:16][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:18]#[CH:17]
Reactant: NC(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCNC(Cc1ccc(Cl)cc1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1-phenyl-2-(4-chlorophenyl)ethylamine (6.00 gm, 2.6×10-2 mol), propargyl bromide (80% in toluene, 4.82 gm, 3.2×10-2 mol), and diisopropylethylamine (5.04 gm, 3.9×10-2 mol) in 50 ml of anhydrous tetrahydrofuran was refluxed at 90° C. under a dry nitrogen atmosphere for four hours. Then, an additional portion of propargyl bromide (0.48 gm, 3.9×10-3 mol) was added, and reflux was continued to another two hours. The reaction mixture was cooled to room temperature, and the resulting white precipitate was removed by filtration. The mother liquor was concentrated on a rotary evaporator, the residue was diluted with 100 ml of diethyl ether, and the resulting white precipitate was again removed by filtration. The etheral mother liquor was quickly extracted with two 50 ml portions of 2N aqueous HCl. Upon standing, the combined aqueous layers yielded the desired intermediate, N-propargyl-1-phenyl-2-(4-chlorophenyl)ethylamine hydrochloride, as an off-white precipitate, which was washed with diethyl ether (4.53 gm, 57%), mp=191°-193°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:6]([C:8](=O)[NH:9][N:10]=2)[N:7]=1.P(Br)(Br)([Br:20])=O.N>>[Br:20][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[C:3]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]nc2cc(N3CCOCC3)c(Cl)nn12
Agent: N
Product: Clc1nn2c(Br)nnc2cc1N1CCOCC1
Temperature: 80 °C
Yield: 43.8 %

Procedure:
A mixture of 6-chloro-7-(morpholin-4-yl)-2 H-1,2,4-triazolo[4,3-b]pyridazin-3-one (1.1 g, 4.3 mmol) and phosphoryl bromide (25 g) was stirred and heated at 80° C. for 24 hours. Upon cooling the mixture was treated with ice. The aqueous was then basified with aqueous ammonia. The aqueous was then extracted with dichloromethane (x3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5% methanol/dichloromethane to give 3-bromo-6-chloro-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (600 mg). 1H NMR and mass spectrum revealed the product to be a mixture of the desired compound and the 6-bromo compound. This mixture was used without further purification. Sodium hydride (60% dispersion in oil, 80 mg, 2.0 mmol) was added in one portion to a stirred solution of the product from above (600 mg) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (240 mg, 2.1 mmol, prepared as described in Example 65) in dry DMF at 0° C. under nitrogen. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and then partitioned between ethyl acetate and water. The aqueous layer was further extracted with dichloromethane (x3). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5 to 8% methanol/dichloromethane to give the title compound (358 mg, 48% for 2 steps). 1H NMR (360 MHz, d6-DMSO) δ3.20-3.22 (4 H, m), 3.69-3.71 (4 H, m), 3.68 (3 H, s), 5.47 (2 H, s), 7.41 (1 H, s), 8.49 (1 Hi s); MS (ES+) m/e 395, 397 [MH+].