Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1.[Cl-].[NH4+].O>[OH:24][C:23]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cccc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Under argon and at −78° C., 4 ml (9.95 mmol) of a 2.5 M solution of n-butyllithium in a hexane fraction were added dropwise to a solution of 1.0 g (4.97 mmol) of 3-bromobenzoic acid in 20 ml of anhydrous THF. After 20 min, 730 μl (9.95 mmol) of acetone were added dropwise at the same temperature. The reaction mixture was stirred at −78° C. for a further hour and then allowed to warm to RT over the course of about 1 h. The reaction mixture was then hydrolysed by careful addition of a few drops of saturated aqueous ammonium chloride solution. The mixture was diluted with 200 ml of water and extracted five times with in each case about 25 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue obtained was purified in four portions by preparative HPLC (Method 36). Pooling of the product fractions, evaporation and drying under high vacuum gave 356 mg (39% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)COc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.1 g of 4-dimethylaminopyridine and 5.1 g (0.025 mole) of 4-chlorophenoxyacetyl chloride are added to 5.1 g (0.025 mole) of 6-(4-amino-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 20 ml of pyridine. The mixture is stirred at room temperature for 5 hours and concentrated, water is added and the mixture is extracted with methylene chloride.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=O)=[CH:6][CH:5]=1)=O.S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[OH2:32]>COCCOCCOC>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[C:23]#[N:24])=[CH:9][CH:8]=1)([O-:12])=[O:32]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C#N)c1ccc([N+](=O)[O-])cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A −15° C. solution of 4-nitroacetophenone (16.5 g, 100 mmol) and tosylmethyl isocyanide (29.3 g, 150 mmol) in methoxyethyl ether (400 ml) was slowly treated with a room temperature solution of the potassium t-butoxide (28 g, 250 mmol) in t-butanole (200 ml). The reaction mixture was stirred at −15° C. for 1 h and then allowed to warm to room temperature over night. Water (100 ml) was added to the mixture and organic was extracted with ether (3×200 ml). The combined organic fraction was washed with water (3×200 ml), brine (100 ml), dried over sodium sulfate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30% EtOAc: Hexane) to give 13.6 g (77%) of the title compound. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=225.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][C:34]=1[F:42])(=O)C.C(OC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1F)(=O)C>>[CH2:1]([N:3]([C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([OH:32])=[C:34]([F:42])[CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1F
Agent: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(OC(C)=O)c(F)c2)c1
Product: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-acetoxy-3-fluorobenzoic acid according to Preparation Example 154 mentioned above, pivalic acid 6-{2-[(4-acetoxy-3-fluorobenzoyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (3.8 g) was used according to an analogous synthetic method to Preparation Example 155 to provide the title compound (2.3 g).
Reaction SMILES: I[CH2:2][CH2:3][C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[C:17](OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=C>>[F:15][C:4]([F:16])([C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:2][CH:18]([CH2:17][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=[CH2:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=CCCCCCCI
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOC(=O)CC(=O)OCC
Product: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane, diethyl malonate and 8-iodooct-1-ene, the analogous procedure as shown in Example 3, 4 or 5 was repeated to give ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21])[NH2:15])([O-:11])=[O:10].CO[C:26](=[O:38])[C:27]([CH3:37])([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[CH3:28]>ClCCCl.C1COCC1>[CH3:37][C:27]1([CH3:28])[N:29]([CH2:30][C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[C:2](=[O:1])[N:15]([C:14]2[CH:16]=[CH:17][C:18]([O:19][C:20]([F:21])([F:22])[F:23])=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[C:26]1=[O:38]
Reactant: COC(=O)C(C)(C)NCc1ccncc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c([N+](=O)[O-])c2)C(=O)N1Cc1ccncc1
Temperature: 50 °C

Procedure:
29 g (146.5 mmol) diphosgene in 300 ml 1,2-dichlorethane were treated at −20° C. with a solution of 13 g (58.6 mmol) 3-nitro-4-(trifluormethoxy)-aniline in 20 ml 1,2-dichlorethane. The mixture was allowed to come to room temperature and then was heated to 50° C. for 3 h. After standing over night, the solvent was evaporated and the residual oil was taken up in 250 ml THF. 13 g (58.6 mmol) 2-methyl-2-[(pyridin-4-ylmethyl)-amino]-propionic acid methyl ester in 250 ml THF were added and the mixture was heated to 40° C. for 1 h. The solvent was evaporated and the residue purified by flash chromatography (Silica gel, methylene chloride:methanol=95:5). Yield: 19.7 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>C1COCC1>[I:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S1(=O)CCN(Cc2ccc(I)cc2)CC1

Procedure:
1-(bromomethyl)-4-iodobenzene (1 g, 3.37 mmol), thiomorpholine 1,1-dioxide (0.546 g, 4.04 mmol) and DIPEA (0.882 mL, 5.05 mmol) were stirred in THF (15 mL) at room temperature overnight. The solvent was removed in vacuo while loading onto silica. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave 4-(4-iodobenzyl)thiomorpholine 1,1-dioxide as a white solid.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1C(=O)O[C@H](C(Cl)(Cl)Cl)O[C@@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2R, 5S, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedure similar to Example 1-(4) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off, and then the residue was subjected to distillation to obtain 0.4 g of isopropyl (2S, 3R)-2-methyl-3-hydroxybutanoate. ##STR41##
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(C=O)cn1
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1

Procedure:
The title compound was prepared from 6-(methylamino)-3-pyridinecarbaldehyde (D95) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D81 in Description D81A. δH (CDCl3, 400 MHz) 7.97 (1H, d), 7.44 (1H, dd), 6.38 (1H, d), 4.51 (1H, m), 4.17 (1H, br.s), 3.79 (1H, d), 3.38 (1H, d), 3.26 (1H, d), 3.07 (1H, td), 2.92 (3H, d), 2.74 (1H, m), 2.57 (1H, m), 2.09 (1H, dd), 1.96 (1H, m), 1.45 (9H, s), 1.20 (3H, d). MS (ES+): 343.2 (MNa+), 265.2, no molecular ion (MH+) observed.
Reaction SMILES: [ClH:1].[CH:2]1([C@@:7](O)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C(N2CCNCC2)=O)CCCC1.[CH3:23][CH2:24]N(C(C)C)C(C)C.C[N:33]([CH:35]=[O:36])C>>[CH2:23]([O:33][C:35](=[NH:36])[CH2:2][CH2:7][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24].[ClH:1]
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(N1CCNCC1)[C@](O)(c1ccccc1)C1CCCC1
Agent: Cl
Product: CCOC(=N)CCc1ccccc1
Temperature: 40 °C

Procedure:
HCl (26 mg, 150 mol) and (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-piperazin-1-ylethanone (43 mg, 150 mol) were combined in DMF (1.0 mL). DIPEA (52 μL, 0.3 mmol) was added, and the mixture was heated at 40° C. for 14 hours. The mixture was then condensed in vacuo and purified by reverse phase HPLC to obtain the title compound as an HCl salt (23 mg, 0.1 mmol, 93.3% purity). MS m/z: [M+H]+ calcd for C26H33N3O2, 420.26; found 420.4.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=O)[CH2:20][CH2:19]1.C[Si](OP(=O)=O)(C)C>O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]2[NH:16][C:14](=[O:15])[C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:13])[C:2]=3[N:1]=2)[CH2:20][CH2:19]1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: Cc1ccccc1-n1ncc(C(N)=O)c1N
Agent: C[Si](C)(C)OP(=O)=O
Solvent: O
Product: Cc1ccccc1-n1ncc2c(=O)[nH]c(CC3CCC(C)CC3)nc21
Temperature: 130 °C
Reaction time: 3 h

Procedure:
150 mg (0.69 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 23A) and 130 mg (0.83 mmol) of 2-(4-methylcyclohexyl)acetic acid are mixed with 3 ml of trimethylsilyl polyphosphate and stirred at 130° C. for 3 h. The hot reaction mixture is added to 20 ml of water and then extracted with dichloromethane (2×20 ml). The combined organic phases are washed with water (20 ml) and with saturated sodium chloride solution (20 ml) and dried over sodium sulphate. The solvent is distilled off under reduced pressure, and the crude product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 182 g (78% of theory) of the product are obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CN(C)C=[O:21]>>[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:21])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc(C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 38 %

Procedure:
4-Fluorobenzonitrile (5 g, 41 mmol, 1 eq.) and 35 mL of dimethylformamide are placed in a 100 mL round-bottomed flask. N-Methylhomopiperazine (5.18 g, 45 mmol, 1.1 eq.) is added to this solution. The solution is heated at a temperature in the region of 90° C. for 36 hours and the solvent is then evaporated to dryness. The residue is diluted with 150 mL of ethyl acetate and 30 mL of water. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After evaporation, the residual oil is purified by chromatography on a column of silica gel, eluting with a 0-10% methanol/dichloromethane gradient (Rf=0.2, 10/90 methanol/dichloromethane (v/v)). The 4-(4-methyl[1,4]diazepan-1-yl)benzonitrile (yellow solid) is placed directly in a mixture of 20 mL of 98% sulfuric acid and 2 mL of water. This orange solution is heated at a temperature in the region of 100° C. for 18 hours, and then cooled and hydrolyzed by pouring it onto ice. The pH is adjusted to 9-10 with sodium hydroxide pellets. The yellow precipitate obtained is filtered off and washed thoroughly with water and then dried under vacuum. 4-(4-Methyl[1,4]diazepan-1-yl)benzamide (3.7 g, 38%) is thus obtained in the form of a yellow solid, which is used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(Cl)(Cl)Cl>C(Cl)Cl>[C:40]([O:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])[CH:24]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC(C)=O)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(5-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 62.5 mg, 0.14 mmol) and triethylamine (154 μL, 1.11 mmol) were dissolved in anhydrous methylene dichloride (1 mL), acetic anhydride (52 μL, 0.55 mmol) was added thereto, and then the mixture was stirred at room temperature for 1.5 hours. Chloroform (10 mL) was added to the reaction mixture, the mixture was washed with water (10 mL) and saturated brine (300 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (56.6 mg) as a colorless amorphous product. (Yield 83%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([Cl:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-Bis-benzyloxy-5-isoproyl-benzoic acid (0.2 g, 0.53 mmol) was dissolved in DCM (10 ml) and treated with oxalyl chloride (1.5 g, 12 mmol) and a catalytic amount of DMF. Stir reaction mixture at room temperature for 14 hours. Solvent was removed in vacuo. The crude material was dissolved in toluene and evaporated. Crude 2,4-bis-benzyloxy-5-isopropyl-benzoyl chloride was obtained as oil (200 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].O>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:9][NH:10][C:11]([NH2:13])=[S:12]
Reactant: O=Cc1ccccn1
Reactant: NNC(N)=S
Solvent: CCO
Solvent: O
Product: NC(=S)NN=Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The corresponding pyridine-2-formaldehyde (23, 23a or 28a-k, 10 mmol) was dissolved in ethanol-water (2:1 v/v, 150 mL). To the solution was added thiosemicarbazide (11 mmol). The solution was stirred for 30 min at ambient temperature. After addition of water (50 mL), the reaction mixture was stirred vigorously for 2 h at room temperature. The yellow precipitate was collected by filtration, washed with ethanol-water (1:4 v/v) and dried in vacuum to afford the corresponding pyridine-2-carboxaldehyde thiosemicarbazone (24, 24a, 29a-k).
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]([NH:27][NH2:28])=O.C(O)CCC>C1(C)C=CC=CC=1>[CH:5]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)=[N:27][N:28]=1)([CH3:7])[CH3:6]
Reactant: CCSC(=Nc1ccccc1)C(C)C
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CC(C)c1nnc(-c2ccc3ccccc3c2)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
First, 5.7 g of N-[1-(ethylsulfanyl)isobutylidene]aniline, 4.4 g of 2-naphthohydrazide, and 40 mL of 1-butanol were put in a 100 mL three-neck flask, and heated and stirred at 120° C. for 20 hours to be reacted. After the reaction, 1-butanol was distilled off to give a brown oily substance. Toluene was added to this oily substance, whereby a solid was precipitated, and then filtrated to give the solid. The resulting solid was recrystallized from toluene, so that 2.7 g of 3-isopropyl-5-(2-naphthyl)-4-phenyl-4H-1,2,4-triazole (abbreviation: HiPrntz) was prepared as a white solid with a yield of 37%. The synthetic scheme of Step 1 is shown by (a-13). As described above, the objective compound of Example 14 has a favorable yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CN.Cl.C[CH2:35][N:36](C(C)C)C(C)C>S(Cl)(Cl)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH:36][CH3:35])(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNS(=O)(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (200 mg, 0.47 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated to reflux for 3 h in an oil bath. The resulting solution was concentrated in vacuo and the residue was diluted by 10 ml of dichloromethane. Then the resulting solution was added dropwise to a solution of MeNH2.HCl (318 mg, 4.75 mmol, 10.00 equiv) and DIEA (917 mg, 7.11 mmol, 15.00 equiv) in dichloromethane (20 mL) at 0° C., and then stirred overnight at room temperature, concentrated in vacuo, and purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 75% in 2.8 min, hold 75% in 2.2 min, up to 100% in 0.1 min, hold 100% in 0.5 min, down to 10% in 0.1 min); Detector, UV 254 nm. This resulted in 100 mg (49%) of 2,3-bis(4-methoxyphenyl)-N-methylquinoxaline-6-sulfonamide as a yellow solid.
Reaction SMILES: [C:1]([O:16][CH2:17][CH2:18][CH2:19][N:20]([C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:46][CH2:47][CH2:48][OH:49]>C(#N)C>[Br-:46].[C:1]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:40](=[O:45])[CH2:41][N+:42]([CH2:47][CH2:48][OH:49])([CH3:43])[CH3:44])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCCCCCCCC)C(=O)CN(C)C
Reactant: OCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCCCCCCCC)C(=O)C[N+](C)(C)CCO
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a sealed system, ((2-(dimethylamino)acetyl)azanediyl)bis(propane-3,1-diyl) ditetradecanoate (246 mg, 0.385 mmol) was dissolved in ACN (10 mL), and 2-bromoethanol (500 uL) was added. The reaction vessel was flushed with inert gas and then sealed. The mixture was heated to 80° C., stirred overnight, and then cooled and concentrated in vacuo. Purification by silica gel chromatography with a DCM/MeOH gradient yielded 99 mg 2-(bis(3-(tetradecanoyloxy)propyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxoethanaminium bromide. QTOF MS ESI+: m/z 683.6 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](OCC)(=O)[CH:14]=[O:15]>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[C:14]([OH:15])[CH:13]=[N:12]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CCO
Product: CC(C)(C)c1ccc2nc(O)cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.4 %

Procedure:
To a solution of 2 g (12.18 mmol) 4-tert-butyl-1,2-diaminobenzene in 20 mL ethanol under argon at room temperature, was added 3.139 mL (15.83 mmol) ethyl glyoxalate (50% in toluene). The reaction mixture was stirred at room temperature for 4 h. The resulting suspension was filtered and washed with ethanol. The powder was dried to provide 257 mg (10.4%) of the title compound as a white solid. MS(m/e): 201.0 (M−H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(O)C>O>[O:18]1[CH:16]([CH2:14][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:17]1
Reactant: Oc1cccc2ccccc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(OCC3CO3)cccc2c1
Yield: 93 %

Procedure:
Into a 500 mL three-necked round bottom flask, 10.03 g 1-naphthol, 3.1 g NaOH, 20.4 g epichlorohydrin (SIR) and 0.5 g KI were added, then 330 mL ethanol was added. The flask was then placed in a microwave reactor. The reaction was performed at 30° C. under stirring and 300 W microwave irradiation for 12 min. The reaction mixture was then removed and suction filtrated, and the filtrate was concentrated to obtain an oily substance. H2O was added to the oily substance, and the mixture was extracted with ethyl ether. The ethyl ether layers were combined and washed with a solution of NaOH, then washed with H2O once. The ether layer was dried using anhydrous magnesium sulfate and concentrated to obtain 12.95 g of the product in a yield of 93.2%.