Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:4].[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:33])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(N(CC)CC)C>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:3](=[O:4])[NH:33][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:22][C@H:13]2[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]2)[CH:32]=[CH:31]3)[CH2:7][CH2:8]1
Reactant: CN1CCC(OC(=O)Cl)CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 11 described in example 138 from triethylamine, 4-chlorocarbonyloxy-1-methylpiperidine hydrochloride (CAS no: 127595-09-9) and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=215.3 (M+H+).
Reaction SMILES: Cl.Cl.[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:30][CH2:31][N:32]([CH3:37])[CH2:33][CH2:34]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Reaction time: 2 h

Procedure:
To a solution of 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.079 mmol, 0.04 g) and aqueous formaldehyde (37%, 0.39 mmol, 0.035 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.47 mmol, 0.20 g). The mixture was shaken for 2 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 4-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.04 g). LCMS: m/z 451 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.63-7.79 (1H, m), 7.38-7.43 (2H, m), 7.10-7.14 (2H, m), 5.33-5.57 (1H, m), 4.40-4.51 (1H, m), 3.66-3.69 (1H, m), 3.11-3.54 (3H, m), 2.94 (3H, s), 2.37-2.62 (2H, m), 2.20-2.30 (1H, m), 1.20-2.17 (22H, m).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=O)C1C=CC=CC=1.[ClH:44].O.[H][H]>CO.[Pd]>[ClH:44].[NH2:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:13][OH:14]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
A solution of 3 g. of Nα -benzyloxycarbonyl-L-seryl-L-tyrosyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol containing 3.7 ml. of 1.35 N hydrogen chloride in methanol is stirred with 200 mg. of 20% palladium on carbon under one inch of water pressure of hydrogen for three hours. Thin layer chromatography of samples of the solution shows disappearance of the starting material in about two hours. The reaction mixture is filtered to remove the catalyst and the filtrate evaporated at 30°-40° C. to yield the product as a foam. The product is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[N+:14]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)([O-:16])=[O:15]>>[CH2:1]([C:3]1([C:22]2[C:21]3[C:25](=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-nitroindole, the title compound is prepared as in example 1. 0.37 g (42%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.18 (m, 2H), 2.35 (m, 1H), 2.53 (m, 1H), 3.00 (m, 2H), 6.83 (t, 1H), 6.92 (t, 1H), 7.01 (m, 2H), 7.08 (s, 1H), 7.44 (d, 1H), 8.09 (d, 1H), 9.76 (s, 1H, NH).
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1cccc(CS)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 3-(mercaptomethyl)benzoic acid (12 g, 71.43 mmol, 1.00 equiv) in acetonitrile (200 mL) was added tert-butyl acrylate (60 mL) and DBU (21.7 g, 142.76 mmol, 2.00 equiv) and the solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 200 mL of water and then adjusted to pH 2˜3 with 10% hydrochloric acid. This was extracted with 3×200 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (50:1) to afford 10.5 g (47%) of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid as red oil. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.08 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.46 (t, 1H), 3.81 (s, 2H), 2.68 (t, 2H), 2.50 (t, 2H), 1.48 (s, 9H). MS (ES, m/z): 295 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl.CN(C)C1C=CN=CC=1>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([N:30]([CH3:34])[CH3:29])=[O:32])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CN(C)C(=O)Cl
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.32 g) obtained in Example 1d) and triethylamine (1.5 ml) in dichloromethane (7 ml) was added dimethylcarbamoyl chloride (0.15 g) under ice-cooling. The mixture was stirred at room temperature for 4 hr, N,N-dimethylpyridin-4-amine (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column (hexane/ethyl acetate=7/3 to ethyl acetate), and the resultant product was recrystallized from ethanol to give the title compound as a colorless powder (0.26 g, 64%).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]=[O:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([OH:18])[CH3:19])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1coc(C=O)n1
Reactant: C[Al](C)C
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)oxazole-2-carbaldehyde (268 mg, 1.11 mmol) in CH2Cl2 (9.2 mL) was treated dropwise at 0° C. with trimethylaluminium (1.11 mL of a 2.0 M solution in toluene, 2.22 mmol) and the resulting yellow solution was stirred for 45 min at 0° C. Sat. aq. NH4Cl was added to the reaction mixture which was extracted with CH2Cl2 (3×25 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.40. LC-MS-conditions 07: tR=0.85 min, [M]+=257.81.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=2)[N:3]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccc(-c3ccccc3)cc2)n1
Yield: 99 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (376 mg). Yield: 99%. 1H NMR (250 MHz, DMSO-d6) δ 7.40-7.60 (m, 5H, Harom), 7.76 (d, 2H, Harom 3+5, J=7.1 Hz), 7.82 (d, 2H, Harom 2+6, J=8.7 Hz), 8.59 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].−
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[N:20][C:15]=2[C:14](=O)[O:13]C1=O>O>[NH2:11][C:16]1[C:15]([C:14]([NH:4][O:2][CH3:3])=[O:13])=[N:20][CH:19]=[CH:18][CH:17]=1
Reactant: CON
Reactant: O=c1[nH]c2cccnc2c(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CONC(=O)c1ncccc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of Methoxylamine hydrochloride (1.02 g, 12.2 mmol) in H2O (5.0 mL) was treated with Potassium carbonate (0.421 g, 3.05 mmol) followed by 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione (J. Med. Chem., 1996, 39, 4962-4703, 1.0 g, 6.1 mmol). This mixture was allowed to stir at 50° C. for ˜1 hour forming a suspension. The ppt was collected via filtration and the filtrate was stored in the freezer O/N allowing an additional 35 mg to be collected. The solids were combined to afford 257 mg of the title compound (22%). 1H NMR (400 MHz, DMSO-d6) d 11.62 (s, 1H), 7.75 (dd, J=1.4, 4.2 Hz, 1H), 7.23 (dd, J=4.2, 8.5 Hz, 1H), 7.15 (dd, J=1.4, 8.5 Hz, 1H), 6.74 (br. s., 2H), 3.65 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:36][NH:37][O:38][CH3:39]>C(Cl)Cl>[CH3:36][N:37]([O:38][CH3:39])[C:16](=[O:18])[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid (2.6 grams, 10 mmol, from Step A) and DIEA (4.4 mL, 25 mmol) in 50 mL CH2Cl2 was cooled to 0° C. Trimethylacetyl chloride (1.4 mL, 11 mmol) was added and the mixture was stirred for 1 h. Solid N,O-dimethylhydroxylamine hydrochloride (1.4 grams, 15 mmol) was added and the mixture was warmed to rt and stirred for 16 h. The solvent was removed and the product was purified by flash chromatography (125 grams silica, 2/1 hexane/EtOAc eluant) to give 1.5 grams (50%) of the title compound. 1H NMR (300 MHz, CDCl3). δ1.05-1.18 (m, 2H), 1.45 (s, 9H), 1.53-1.75 (m, 4H), 2.4-2.5 (t, 2H), 2.6-2.77 (m, 2H), 3.18 (s, 3H), 3.63 (s, 3H), 4.0-4.15 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[OH:36])[O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:19][C:18]=1[CH3:32])[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[OH:36])[O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:19][C:18]=1[CH3:32])[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(CN(Cc3ccccc3)C(C)C)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc(O)c(CN(Cc2ccccc2)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl {[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate (50 mg, 0,10 mmol) and NaOH (40 mg, 1.02 mmol) are dissolved in dioxane/water (0.5 1, 1:1 v/v) and stirred at room temperature for 1 h. The reaction mixture is partitioned between ethyl acetate and potassium dihydrogen phosphate/disodium hydrogen phosphate buffer solution (pH 7), and the organic phase is salted out with NaCl, filtered and evaporated. The resulting crude product is purified by preparative RP-HPLC with a water/acetonitrile/TFA eluent.
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1)(=O)=O>CN(C)C=O.O>[CH3:1][S:2][CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CSC)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Sodium methanethiolate (4.36 g, 62.30 mmol) was added to a stirred solution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (6.92 g, 31.10 mmol) in N,N-dimethylformamide (62.30 mL) at 23° C. The resulting brown suspension was stirred at 23° C. for 18 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic layers were dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (5.43 g, 100%): 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][C:21](=[O:23])[CH3:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:21](=[O:23])[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 88.5 %

Procedure:
To a 100 ml volume three-necked flask, sodium p-toluenesulfinate (20-a) (9.25 g), tetrabutylammonium bromide (1.65 g), toluene (29 g), and chloroacetone (21-a) (5.0 g) were added, and stirred at 65° C. for 1.25 hours. To the mixture, water (10 g) was added, and stirred for 4 hours. After the mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted with toluene 2 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (chloroform: ethyl acetate=20:1) to give 9.749 g of 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[Na]>C(O)C>[N:8](/[C:11](=[CH:6]\[C:5]1[S:1][CH:2]=[N:3][CH:4]=1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10]
Reactant: O=Cc1cncs1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1cncs1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
To a solution of thiazole-5-carbaldehyde (20 g, 176.77 mmol) and ethyl 2-azidoacetate (91.2 g, 707.1 mmol) in anhydrous ethanol (100 mL) was added sodium (16.26 g, 707.1 mmol) dissolved in anhydrous ethanol (1000 mL) dropwise between −10° C. and 0° C. After the addition, the mixture was stirred below 0° C. for 4 hours, and then warm to the ambient temperature and allowed to stir overnight. The reaction mixture was washed with saturated ammonium chloride, extracted with acetic ester (500 mL×3), the combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 20:1→10:1) to afford the title compound (9 g, 23%) as an yellow solid. LCMS (M+H+) m/z: calcd. 224.04. found 224.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[C:8](\[CH2:11][CH3:12])/[CH2:9][OH:10])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[C:8](\[CH2:11][CH3:12])/[CH:9]=[O:10])=[CH:5][CH:4]=1
Reactant: CC/C(=C\c1ccc(OC)cc1)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC/C(C=O)=C\c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.1 %

Procedure:
A mixture of 2-((E)-4-methoxybenzylidene)butan-1-ol (13 g) and manganese dioxide (130 g) in chloroform (600 ml) was stirred at room temperature for 20 hours. Manganese dioxide was filtered off by filtration and the filtrate was condensed to give 2-((E)-4-methoxybenzylidene)butan-1-al (9.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CN(C=O)C>O>[CH2:31]([N:12]1[C:11](=[O:23])[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
A mixture of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-one (2.14 g, 6.9 mmol), freshly ground potassium carbonate (1.45 g, 10.5 mmol), 1.43 g of iodopentane (7.2 mmol) and 11 mL of DMF were stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and stripped. Column chromatography gave 0.4 g of Compound 8.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([NH:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[C:20]=2[CH3:27])=[O:17])[CH:10]=[CH:11][C:12]=1[F:13].C(N(CC)C(C)C)(C)C.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:25][C:21]2[C:20]([CH3:27])=[C:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][C:9]3[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1c(CO)cccc1NC(=O)CNc1ccc(F)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2cccc(NC(=O)CNc3ccc(F)c(F)c3)c2C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methane sulphonyl chloride (0.06ml) was added to a solution of the product of step (d) (0.12 g) and N,N-diisopropylethylamine (0.28 ml) in tetrahydrofuran (3ml). The reaction mixture was stirred at room temperature for 1.5 hours. A solution of 1-acetylpiperazine (0. 15 g) in tetrahydrofuran (1 ml) was added and the mixture was heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The crude product was triturated with ethyl acetate/isohexane to give the product as a pale yellow solid.
Reaction SMILES: O([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])S(C(F)(F)F)(=O)=O.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:47])[C:25]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]([C:44]#[N:45])[C:42]#[N:43])=[CH:37][CH:36]=2)=[CH:28][C:27]=1[CH3:46].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:19][C:20]1[C:25](=[C:26]2[C:27]([CH3:46])=[CH:28][C:29](=[CH:33][CH:34]=[C:35]3[CH:40]=[CH:39][C:38](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[CH:37]=[CH:36]3)[CH:30]=[C:31]2[CH3:32])[C:24]([CH3:47])=[CH:23][N:22]([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:21]=1
Reactant: CCCCCC(CCC)COS(=O)(=O)C(F)(F)F
Reactant: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=CC=c3ccc(=C(C#N)C#N)cc3)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL), and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give nearly pure 2-propyl-1-heptyl triflate as purple liquid (1.40 g, 94.1%). Next, 2-propyl-1-heptyl triflate (0.319 g, 1.10 mmol) was added dropwise to a solution of 19 (0.377 g, 1.00 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 4 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 20. The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (50 L) and CH2Cl2 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 4:100 methnol: CH2Cl2, to give 0.340 g (65.7%) of the title compound as purple solid: mp 161-162° C.; NMR (400 MHz, DMSO-d6): δ 9.039 (s, 2H), 7.418 (s, 2H), 7.286 (d, 2H, J=8.0 Hz), 7.145 (d, 1H, J=16.4 Hz), 6.919 (d, 1H, J=16.4 Hz), 6.739 (d, 2H, J=7.6 Hz), 4.453 (m, 2H, J=5.2 Hz), 2.125 (m, 1H), 2.074 (s, 6H), 1.859 (s, 6H), 1.319-1.219 (m, 12H), 0.849 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 157.523, 142.592, 141.882, 138.688, 136.859, 133.320, 131.364, 129.981, 126.942, 125.704, 125.468, 121.582, 118.070, 64.195, 38.546, 32.695, 31.366, 30.156, 29.419, 25.061, 21.894, 19.010, 18.855, 16.581, 14.215, 13.942; MS (high resolution, EI): m/z 517.3451 [M+]; calcd, 517.3457; Anal. Calcd. for C36H43N3.1/3H2O: C, 82.56; H, 8.40; N, 8.02. Found; C, 82.59; H, 8.11; N, 8.36.