Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=1[O:16][CH3:17])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(OC)c(C(=O)c2cc(Cl)ccc2N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(O)c2cc(Cl)ccc2N)c(OC)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 3.0 g of 2-amino-5-chloro-2',4',6'-trimethoxybenzophenone in 50 ml of tetrahydrofuran, 0.43 g of lithium aluminum hydride was added, followed by stirring for 1 hour. After water was added, the solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate, after which the solvent was removed and the residue was subjected to silica gel column chromatography to yield 2.9 g of a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)=[O:5].[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)c2ccccc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(NC(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
A mixture of 1.52 g of ethyl 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylate, 0.68 g of potassium hydroxide, 1.8 mL of water and 9 mL of ethanol was stirred at room temperature for 4 hrs. After the reaction mixture was diluted with water, it was washed with ethyl acetate. The separated aqueous phase was acidified with an aqueous 2N-hydrochloric acid solution and the precipitated crude product was washed with water and dried to obtain 0.96 g of the aimed 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].I[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: ICCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCCN2CCOCC2)c1
Temperature: 80 °C

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (143 mg) and 4-(2-iodoethyl)morpholine.HCI (189 mg) were combined in DMF (10 ml). Sodium hydride (55 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. under nitrogen for 5 hours. The reaction was quenched with water (10 ml) and the solvent evaporated under vacuum. Ethyl acetate/chloroform (1:1, 30 ml) and water (30 ml) were added to the residue resulting in precipitation of a solid, which was filtered off and washed with ether. The solid was partitioned between ethyl acetate/chloroform (1:1, 2×50 ml) and aqueous sodium hydrogen carbonate solution (1 M, 50 ml). The organic layers were combined, dried over a hydrophobic filter and evaporated to give methyl 4-bromo-3-{[2-(4-morpholinyl)ethyl]oxy}benzoate as a yellow gel (103 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCNCC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 50 ml of diethylamine, a reaction similar to that conducted in Example 107 was carried out. As a result, 4.75 g of N-(trans-4-methylcyclohexyl)-4-(2-diethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>CN(C=O)C.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a suspension of 2-nitro-6(5H)-phenanthridinone (3.8 g, 0.0 16 mol) in DMF (200 mL) was added an ammonium chloride solution (3%, 200 mL), followed by the addition of iron powder (22 g). The reaction mixture was stirred at 100° C. for 1 hr. The residue was removed by filtration, and the filtrate was made acidic by adding dilute HCl (25%, 20 mL). A solid separated from the solution and was filtered and washed thoroughly with cold water to remove acidic impurities. The solid was then dried under vacuum, to give hydrochloride salt of 2-amino-6(5H)-phenanthridinone (3.4 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13][C:14](C)([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+].C1(=O)CCC1>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[C:14]4([CH2:16][CH2:24][CH2:15]4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C1CCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2(CCC2)C2c3ccccc3Oc3ccc(Cl)cc3N12
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of 1.0 g (3.0 mmol) of 1 in 20 mL of anhydrous THF was added 1.2 equivalent of lithium diisopropylamide at -78°. After 30 minutes, approximately 2 equivalent of cyclobutanone was added as the electrophile. The stirring was continued for 3 hours at -78°, followed by room temperature overnight, and was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with brine and dried with magnesium sulfate or sodium sulfate. Purification by HPLC on silica gel with 7% ethyl acetate/hexane as the eluent followed by lyophilization from acetonitrile/water gave 355 mg (36%) of Compound 21. 1H NMR (CDCl3): δ7.62 (s, 1H, ArH), 7.16-7.40 (m, 6H, ArH), 5.19 (s, 1H, ARCH), 2.75-2.84 (m, 1H, c-butyl), 2.45-2.60 (m, 1H, c-butyl), 2.28-2.42 (m, 1H, c-butyl), 2.12- 2.26 (m, 1H, c-butyl), 1.82-2.00 (m, 1H, c-butyl), 1.30-1.45 (m, 1H, c-butyl). FABMS: m/z 334 (M+Li). HRMS calculated for C18H14NO3LiCl (M+Li) 334.0822, found 334.0867. Analysis Calculated for C18H14NO3Cl: C, 65.96; H, 4.31; N, 4.27; Cl, 10.82. Found: C, 65.86; H, 4.31; N, 4.31; Cl, 10.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:15]([CH:28]=[CH2:29])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:28]([C:15]1[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:17]([C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:13][CH:14]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:29]
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OC)c1OCC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OC)c1OCC(=O)OC

Procedure:
A mixture of Example 467C (0.31 g, 0.7 mmole) in methanol (10 mL) was treated with 10% Pd/C (100 mg) at ambient temperature under one atmosphere of hydrogen for 16 hours. Filtration and evaporation of the solvent provided the desired product. 0.29 g, 97.5%. 1H NMR (DMSO-d6) δ 1.10 (t, 3H), 2.54 (q, 2H), 3.64 (s, 3H), 3.70 (s, 3H), 4.48 (s, 2H), 6.85 (d, 1H), 7.28 (d, 1H), 7.40 (t, 2H), 7.70 (t, 2H), 9.86 (s, 1H); MS (ESI(−)) m/e 424 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[CH:11]=[CH:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C@H:3]1[C:12](=[O:16])/[CH:13]=[CH:14]/[CH3:15]>C(O)C.[Pd]>[CH3:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C@H:3]1[C:12](=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)[C@H]1[C@H](C)CCCC12CCCC2
Yield: 36.8 %

Procedure:
A solution of (E)-1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (2.0 g, 9.16 mmol) in ethanol (30 ml) was treated with 10% Pd/C (0.4 g) and hydrogenated (20 bar) for 1.5 h. The resulting mixture was filtered and concentrated. FC (SiO2, hexane/MTBE 50:1) of the crude product (1.9 g) gave 1-(rel-(6S,7R)-7-methylspiro[4.5]decan-6-yl)butan-1-one (0.75 g, 37%). Boiling point: 95° C. (0.08 mbar).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH2:22])[CH2:2][CH2:3][CH3:4].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH:22][C:30](=[O:31])[CH2:29][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(N)cnn1-c1ncc(C)c(-c2cccs2)n1
Reactant: O=C(O)Cc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1c(NC(=O)Cc2ccncc2)cnn1-c1ncc(C)c(-c2cccs2)n1
Temperature: 40 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a solution of 5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-amine (51 mg, 0.163 mmol, 1.0 equiv) and 2-(pyridin-4-yl)acetic acid (56 mg, 0.323 mmol, 2.0 equiv) in DMF (1 mL) was added HBTU (51 mg, 0.179 mmol, 1.1 equiv) and DIEA (91 μL, 0.520 mmol, 3.2 equiv) and heated to 40° C. and let stir for 15 h. The reaction was diluted with saturated NaHCO3 solution (15 mL) and extracted with a solution of 30% IPA in CHCl3 (3×20 mL). The organic layer dried (sodium sulfate), concentrated, and the residue was purified by silica gel flash column chromatography (10% methanol in dichloromethane) afford 35 (45 mg, 64% yield) as an off-white amorphous solid. 1H NMR (400 MHz, CD3OD) δ 8.65 (s 1H), 8.51 (d, J=5.6 Hz, 2H), 7.91 (d, J=4.4 Hz, 2H), 7.75 (d, J=5.2 Hz, 1H), 7.48 (d, J=5.6 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 3.83 (s, 2H), 3.22 (t, J=7.6 Hz, 2H), 2.60 (s, 3H), 1.48 (quint, J=7.6 Hz, 2H), 1.25 (sex, J=7.2 Hz, 2H), 0.77 (t, J=7.2 Hz, 3H). LCMS (ES+) m/z 433 (M+1).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[N+:8]([O-])[C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>C(O)C.[Ni]>[N:1]1([C:6]2[N:7]=[N:8][C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: [O-][n+]1nc(-n2cccn2)nc2ccc(Cl)cc21
Agent: [Ni]
Solvent: CCO
Product: Clc1ccc2nc(-n3cccn3)nnc2c1

Procedure:
24.8 g (0.1 mol) of 3-pyrazol-1-yl-7-chloro-benzo-1,2,4-triazine 1-oxide were hydrogenated in 150 ml of ethanol at 25° to 30° C. in the presence of Raney nickel under a hydrogen pressure of 50 bars, until the pressure remained constant. The catalyst was filtered off and the solution was evaporated in vacuo. 3-(Pyrazol-1-yl)-7-chloro-benzo-1,2,4-triazine of melting point 188° C. was obtained in virtually quantitative yield. The compound could be recrystallized from toluene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C)C>C(Cl)Cl>[CH:2]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23](=[O:36])[C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][CH:29]=3)[CH:9]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C=O)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Yield: 24 %

Procedure:
Following the same procedure as described in Example 20, step 6 (scheme 20), but substituting compound 190 for compound 199, title compound 200 was obtained in 24% yield [after column chromatography (eluent: 5% isopropanol in DCM)].
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C[O:17][C:18]1C=C[CH:21]=[CH:20][C:19]=1N1CCN(CCCCO)CC1>>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH2:19][CH2:18][OH:17])[CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCN(CCCCO)CC1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Product: OCCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 81 %

Procedure:
4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butan-1-ol (37A) is prepared from 1-(2,3-dichloro-phenyl)-piperazine hydrochloride as described for 30A.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[CH:18]=1.NC1C2N(C=C(C)N=2)C=CC=1.C([Cl:36])(=O)C(C)(C)C.ClCl>C(O)(=O)C>[Cl:36][C:18]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[C:5]2=[N:4][C:3]=1[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cn2cccc(NC(=O)C(C)(C)C)c2n1
Agent: Cc1cn2cccc(N)c2n1
Agent: Cl
Agent: ClCl
Solvent: CC(=O)O
Product: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1Cl
Yield: 83 %

Procedure:
5.0 g (18.6 mmol) of 2-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine hydrochloride, prepared from 8-amino-2-methylimidazo[1,2-a]pyridine and pivaloyl chloride, m.p. 229-230° C., are dissolved in glacial acetic acid (20 ml) and chlorine gas is slowly passed in at 15° C. until the reaction has ended according to TLC checking (about 20 min). The solvent is then distilled off, the residue is taken up in ethyl acetate/water (in each case 30 ml), and the solution is rendered basic and extracted with saturated sodium hydrogen carbonate solution. The extract is then extracted again with ethyl acetate (3×30 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene/dioxane=9:1). After concentration of the fractions of Rf =0.2, the title compound (4.1 g, 83%) is obtained as a colorless solid. M.p. 117-118° C.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([CH3:12])([CH3:11])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]([CH3:11])([CH3:12])[S:4]1)=[O:16]
Reactant: CC(C)C1=NC(=NO)SC1(C)C
Reactant: CN=C=O
Product: CNC(=O)ON=C1N=C(C(C)C)C(C)(C)S1

Procedure:
2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 89°-91° C. The 2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-oxime starting material (m.p. 220°-222° C.) was prepared from 2,4-dimethyl-2-thiocyanato-3-pentanone (b.p. [0.02 mm] 64°-66° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:17][CH:18]([N+:30]([O-:32])=[O:31])[C:19]([CH3:29])([CH3:28])[CH2:20][C:21](=[O:27])[CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:17][CH:18]([N+:30]([O-:32])=[O:31])[C:19]([CH3:29])([CH3:28])[CH2:20][C:21](=[O:27])[CH:22]([O:25][CH3:26])[O:23][CH3:24])[NH:5][CH:6]=1
Reactant: COC(OC)C(=O)CC(C)(C)C(Cc1c(C)c(Br)cn1S(=O)(=O)c1ccc(C)cc1)[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)CC(C)(C)C(Cc1[nH]cc(Br)c1C)[N+](=O)[O-]
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Following a general procedure,50 a sample of 6-Ts (9.12 g, 16.7 mmol) was treated with TBAF (34 mL, 1.0 M in THF, 34 mmol), and the reaction mixture was stirred for 1 h at reflux. A saturated solution of aqueous NaHCO3 (100 mL) was added followed by ethyl acetate (50 mL). The mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), concentrated to a brown oil, dried under high vacuum for 2 h, and chromatographed (silica, CH2Cl2) to give a light brown oil (4.00 g, 61%): 1H NMR δ 1.13 (s, 3H), 1.22 (s, 3H), 1.95 (s, 3H), 2.60, 2.70 (AB, 2J=18.8 Hz, 2H), 2.99 (ABX, 2JAB=15.4 Hz, 3JBX=2.5 Hz, 1H), 3.24 (ABX, 2JAB=15.4 Hz, 3JAX=11.8 Hz, 1H), 3.41 (s, 3H), 3.42 (s, 3H), 4.38 (s, 1H), 5.12 (ABX, 3JAX=11.8 Hz, 3JBX=2.5 Hz, 1H), 6.59 (s, 1H), 8.29 (brs, 1H); 13C NMR δ 9.8, 24.4, 24.4, 25.6, 36.6, 45.4, 55.39, 55.40, 94.1, 99.0, 104.7, 116.1, 116.7, 122.5, 204.2; ESI-MS obsd 391.0864, calcd 391.0863 [(M+H)+, M=C15H23BrN2O5].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 0 °C
Yield: 55.2 %

Procedure:
The 1-aryl-2-nitropropenes were prepared according to the procedure of Koremura, Oku, Shono and Nakanishi (6). The starting aldehydes, commercially available, were used without further purification. To prepare 1-(2,4-dichlorophenyl)-2-nitropropene, a mixture of 43.5 g (0.25 mol) of 2,4-dichlorobenzaldehyde, 18.75 g (0.25 mol) of 1-nitroethane, and 20 g of ammonium acetate, dissolved in 100 ml of glacial acetic acid, was refluxed for two hours, and then poured onto 200 g of ice. The yellow precipitate was collected and recrysallized from absolute ethanol to give 32 g (60%) of 1-(2,4-dichlorophenyl)-2-nitropropene mp 75°; ir (KBr) 1661 (C=C), 1520 and 1319 cm-1 (NO2).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)=[CH:9][N:10]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)=[CH:9][N:10]=1
Reactant: COCc1ncc(Cn2ncc([N+](=O)[O-])n2)s1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1ncc(Cn2ncc(N)n2)s1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(methoxymethyl)-5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole (109 mg, 0.43 mmol), iron powder (72 mg, 1.28 mmol) and NH4Cl (115 mg, 2.14 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (5 mL) was added followed by 1N NaOH (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×5 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.50 min; [M+H]+=225.93.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:6]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>N1C=CC=CC=1.ClCCl>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:6]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCC(=O)NCC1Cc2cccc(N)c2C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
N-(4-Amino-indan-2-ylmethyl)-propionamide (0.51 g, 2.34 mmol) was dissolved in pyridine-dichloromethane (1:2, 30 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (0.54 g, 2.47 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give the product as a brown oil (0.95 g, 100%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].Cl.Cl.CN1C=C(CCN)N=C1.N1C=CN=C1>ClCCl>[CH:6]1[N:5]=[CH:4][N:3]2[C:7]=1[CH2:11][CH2:12][NH:8][C:1]2=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: Cn1cnc(CCN)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: O=C1NCCc2cncn21
Temperature: 22 °C

Procedure:
Carbonyldiimidazole (970.2 g) was added to a stirred suspension of [2-(1-methyl-1H-imidazol-4-yl)ethyl]amine dihydrochloride (999.9 g) (commercial eg Sigma) and imidazole (37 g) in dichloromethane (5.3 litres) at ca 22° C. The resulting white suspension was heated at reflux until reaction was complete by nmr (4 h.). Solvent (8 litres) was distilled off at atmospheric pressure whilst adding IMS-G (8 litres). Additional IMS-G (2 litres) was added and the suspension cooled to ca. 22° C. and aged at this temperature for at 2 h. The solid was collected by filtration, washed with IMS-G (2×0.5 litres), pulled dry and dried in vacuo at ca. 60° C. to yield the title compound, 478 g.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](I)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:27][C:28]1[C:33]([C:34]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=[C:30]([CH3:42])[N:29]=1>O1CCCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:34]([C:33]3[C:28]([CH3:27])=[N:29][C:30]([CH3:42])=[CH:31][CH:32]=3)([C:36]3[N:40]([CH3:41])[N:39]=[N:38][CH:37]=3)[OH:35])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.79 mL, 1.0 mmol) was added dropwise to an ice-water cooled, stirring solution of 3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (325 mg, 0.682 mmol, Intermediate 20: step c) in dry tetrahydrofuran (5 mL). After 15 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (177 mg, 0.818 mmol, Intermediate 19: step b) in tetrahydrofuran (1.5 mL) was added dropwise. After 10 minutes, the flask was removed from the cooling bath and allowed to warm to 23° C. After 4 hours, water (5 mL) was added. The mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as a white solid. MS (ESI): mass calcd. for C30H27ClN8O2, 566.2. m/z found, 567.0 [M+H]+.