Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[N:19]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[N:12]2[N:11]=1.CN(C)C=O.[C:25]1([C:31]2[N:32]=[C:33]([SH:36])[NH:34][N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-]>CCOC(C)=O>[CH3:18][C:17]1[N:12]2[N:11]=[C:10]([CH2:9][S:36][C:33]3[NH:34][N:35]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:32]=3)[N:19]=[C:13]2[CH:14]=[CH:15][CH:16]=1
Reactant: Sc1nc(-c2ccccc2)n[nH]1
Reactant: Cc1cccc2nc(CCl)nn12
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(CSc3nc(-c4ccccc4)n[nH]3)nn12
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
Triethylamine (0.7602 mL, 5.454 mmol) was added to a solution of [2-Chloromethyl-5-methyl-(1,2,4]triazolo[1,5-a]pyridine (495 mg, 2.73 mmol) in N,N-Dimethylformamide (12 mL, 150 mmol) and the solution was stirred aprox 2 mins. 5-Phenyl-2H-1,2,4-triazole-3-thiol (532 mg, 3.00 mmol) was added to the mixture as a solid. The reaction mixture was subsequently heated at 60° C. for 0.5 hours. The mixture was rotovaped. EtOAc (60 mL) and sat. bicarbonate (20 mL) were added to the residue and the phases were separated. The organic phase was washed with brine (20 mL). After drying (MgSO4), the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Eluent: EtOAC:N-heptane 50-100%). This afforded 542 mg (61%) of the title compound as a white solid. LC-MS: m/z=323.1 (MH+), tR=0.52 min, Method B. 1H NMR (600 MHz, DMSO-ds): δ 7.96 (d, 2H), 7.63 (m, 1H), 7.60 (t, 1H) 7.50 (m, 3H), 7.06 (d, 1H), 4.68 (s, 2H), 2.67 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCCCCCO)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCCCCOS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a solution of the compound 24 (3.58 g) and triethylamine (2.76 mL) in ethyl acetate (50 mL), methanesulfonyl chloride (0.78 mL) was slowly added under ice cooling. The reaction mixture was stirred under ice cooling for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The diluted solution was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0→10:1) to obtain the title compound (3.70 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=1)=[O:32]
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1F
Temperature: 25 °C
Yield: 40.6 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-2'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid which was purified by flash column chromatography (5% v/v ethyl ether/methylene chloride). Recrystallization of the resulting solid from hexane yielded the title propanamide as a tan solid (0.83 g, 40%); mp 137°-139° C. 1H-NMR (300 MHz, d6-DMSO): 7.36-7.42 (m, 2H, aromatic) 7.54-7.60 (m, 1H, aromatic) 7.63-7.69 (m, 1H, aromatic) 7.76-7.79 (m, 2H, aromatic) 7.92-7.96 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.86 (bs, 1H, OH). MS (CI, CH4): 410 (M+1). Analysis for C17H10F7NO3 : Calculated: C, 49.89; H, 2.46; N, 3.42. Found: C, 50.05; H, 2.46; N, 3.36.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7][OH:8].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1C=CC=CC=1>[CH2:16]([O:8][CH2:7][CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5][N:4]([CH3:10])[CH3:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN(C)CC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.6 %

Procedure:
To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 mL), brine (2×200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1H NMR (400 MHz, CDCl3) δ: 5.35 (8H, m, CH═CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2×CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2×NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2×CH2), 1.28 (32H, m, 16×CH2), 0.88 (6H, t, 2×CH3) ppm.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:37]([O:39][CH2:40][C:41](Cl)=[O:42])[CH3:38]>ClCCl>[CH2:37]([O:39][CH2:40][C:41]([NH:8][C:9]1[C:10]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:42])[CH3:38]
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(Oc2ccccc2)nc(C)c(C)c1NCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamate as a brown oil. The oil was combined with pyridine (130 mL) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to provide 8.21 g of tert-butyl 4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1.O>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C(=O)c1ccccc1)CC2
Yield: 95 %

Procedure:
0.01 mole (2.7 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 50 ml of benzene under slight warming, and the solution obtained is admixed with a solution of 0.015 mole (0.6 g) of sodium hydroxide in 10 ml of water. 0.011 mole (1.5 g) of benzoyl chloride is added dropwise to the reaction mixture under cooling and stirring. When the addition is complete, the reaction mixture is stirred at room temperature for an additional hour, the organic phase is separated, and the aqueous phase is extracted twice with chloroform. The organic phases are combined, dried and evaporated to yield the aimed compound with a melting point of 161° to 163° C. (methanol/ether).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH:25]1([CH2:28][NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[C:35]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:36]=2)=[O:47])[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.46 min, MH+ 498. NMR: δH [2H6]-DMSO 11.67,(1H, b), 9.24,(1H, s), 8.63,(1H, t), 8.39,(1H, d), 8.32,(1H, d), 7.97,(1H, s), 7.88–7.83,(2H, m), 7.45,(1H, d), 7.36,(1H, t), 7.30,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 3.15,(2H, t), 2.70–2.21,(11H, m), 1.04,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]([CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Oc1ccccc1
Product: Clc1cncc(N2CCN3CC(COc4ccccc4)CCC3C2)n1

Procedure:
A mixture of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 2,6-dichloropyrazine were combined according to Preparation 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (—HCl) 247° C. (dec). HRMS calc for C19H23ClN4O: 358.1560, found: 358.160
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.F[C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][CH:19]=1.[NH2:23][C:24]1[N:29]=[C:28]([N:30]([CH3:38])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33](C)[CH:32]=2)[N:27]=[C:26]([C:39]([NH:41]O)=[NH:40])[N:25]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>N1C=CC=CC=1.CCOC(C)=O>[CH:43]1([NH:46][C:14]2[C:15]([C:20]3[O:22][N:40]=[C:39]([C:26]4[N:27]=[C:28]([N:30]([CH3:38])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:29]=[C:24]([NH2:23])[N:25]=4)[N:41]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:45][CH2:44]1
Reactant: NC1CC1
Reactant: O=C(O)c1ncccc1F
Reactant: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3NC3CC3)n2)n1
Reaction time: 1 h
Yield: 17 %

Procedure:
1,1′-Carbonyldiimidazole (62 mg, 0.380 mmol) was added to a solution of 3-fluoropyridine-2-carboxylic acid (50 mg, 0.354 mmol) in anhydrous pyridine (1 mL) in a sealed tube at room temperature and the mixture was stirred for 1 h. 4-Amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidine (prepared in an analogous manner to Intermediate 1, 66 mg, 0.253 mmol) was added and the mixture was stirred at room temperature for 60 min and then at 90 C for approximately 18 h. The mixture was then treated with cyclopropanamine (300 μL, 4.32 mmol) and stirred at 80 C for 7 h. The mixture was then diluted with EtOAc (35 mL) and washed with water (10 mL), saturated aq. ammonium chloride (2×6 mL) and 2M hydrochloric acid (3×5 mL). The combined hydrochloric acid extractions were washed with DCM (2×6 mL) and then made alkaline by the addition of 2M aq. sodium hydroxide. The resulting solution was extracted with DCM (4×7 mL), the combined organic extractions were washed with brine (10 mL), dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-3% MeOH in DCM) to afford the title compound (17 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]=O>OS(O)(=O)=O>[CH3:12][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CNc1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
15.2 g of 2-methyl-4-nitroaniline were dissolved in 150 ml conc. H2SO4 and heated in a boiling water bath. To this solution 24 g. of paraformaldehyde were added with stirring over a period of 10 minutes. The mixture was stirred an additional hour and was then cooled and poured over 300 g of ice. The precipitate was recrystallized from ethanol water to give 10.1 g of N,2-dimethyl-4-nitroaniline (m.p. 133°-136°C).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[Na+]>CN(C)C=O>[CH2:11]([O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:9])[CH3:12]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of ethyl salicylate (10.0 g, 60.2 mmol), 60% sodium hydride (2.41 g, 60.2 mmol) and N,N-dimethylformamide (150 ml) w as stirred at room temperature for about 1 hour, followed by adding dropwise thereto ethyl 4-bromobutyrate (12.9 g, 66.2 mmol). The reaction mixture was stirred at room temperature for 4.5 hours and then at 65-70° C. for 2 hours. The reaction mixture was poured into a cooled 5% aqueous sodium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:95) to obtain 16.4 g of ethyl 4-(2-ethoxycarbonylphenyloxy)butyrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45].CN(C)P(=[O:55])(N(C)C)N(C)C.CN(C)CCN(C)C.C([Li])CCC>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([OH:55])=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(O)c(OC)c2OCOC)c(OC)c1OCOC
Reaction time: 0.5 h

Procedure:
Under argon gas stream conditions 2 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene was dissolved in 50 ml of a mixed solvent of anhydrous toluene-tetrahydrofuran (4:1), to this solution were added 10 ml of hexamethylphosphoric triamide and 0.94 ml of N,N,N',N'-tetramethylethylenediamine, then the whole mixture was cooled on a dry ice-acetone bath. 4 Milliliter of n-butyllithium (1.5 M, n-hexane solution) was added dropwise to the reaction mixture and stirred 30 minutes. Next, oxygen gas was bubbled into the reaction mixture for 30 minutes, then the temperature of the reaction mixture was returned back to room temperature by taking for 4 hours. The reaction mixture was concentrated, to the residue obtained was added 100 ml of ethyl acetate, then the ethyl acetate layer was washed twice with 30 ml of a saturated sodium bisulfite aqueous solution, once with 30 ml of water, further washed once with 30 ml of a saturated sodium chloride aqueous solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated, then the residue obtained was purified by a silica gel column chromatography (eluent: ethyl acetate-n-hexane=1:9) to obtain 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-hydroxyphenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [N+:1]1([O-:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[F:10][B-:11]([F:14])([F:13])[F:12].[CH3:15][O+](C)C>ClCCl>[F:10][B-:11]([F:14])([F:13])[F:12].[CH3:15][O:9][N+:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8]
Reactant: C[O+](C)C
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[n+]1c(C)cccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-lutidine N-oxide (24.0 g, 0.20 mol) in anhydrous dichloromethane (400 mL) was added to trimethyloxonium tetrafluoroborate (29.6 g, 0.20 mol) at room temperature under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo to give the crude product, 1-methoxy-2,6-dimethyl-pyridinium tetrafluoroborate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14]Cl)[C:7]=2[CH:16]=1)#[N:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:28]3[CH2:27][CH2:26][N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=4)[CH2:30][CH2:29]3)[C:7]=2[CH:16]=1)#[N:2]
Reactant: N#Cc1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
6-cyano-1-(4-chlorobutyl)-1H-benzotriazole (8.42 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.5 g compound (I-55) with a yield of 66.4%. ESI-MS [M+H]+: m/z 428.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[C:3]=1[OH:33].[C:34](Cl)(=[O:39])[CH2:35][C:36](Cl)=[O:37].O.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:9][C:6]1[C:7]2=[N:8][C:34](=[O:39])[CH2:35][C:36](=[O:37])[N:1]=[C:2]2[C:3]([OH:33])=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[CH:5]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)c(N)c1O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2

Procedure:
In 250 ml of benzene was dissolved 17 g of the resulting 2,3-diamino-4-chloro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol, and a solution of 5.8 g of malonyl dichloride in 100 ml of benzene was slowly added to the solution at room temperature while stirring. After the dropwise addition, the reaction mixture was stirred for 1 hour. Water and ethyl acetate were added to the reaction mixture to effect extraction. The extract was concentrated, and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=2/1 by volume) to obtain 4.2 g of the desired coupler (Coupler 3) having a melting point of 193° to 195° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:24](OCC)[O:25]CC)=[N:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:6]([F:16])[C:7]=1[N:8]=C1C=CC(=O)C=C1.S(=O)(=O)(O)O.C(Cl)Cl>C(#N)C.O>[NH2:8][C:7]1[C:6]([F:16])=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=[C:3]([CH:24]=[O:25])[C:2]=1[Cl:1]
Reactant: CCOC(OCC)c1nc(-c2ccc(Cl)cc2)c(F)c(N=C2C=CC(=O)C=C2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Nc1c(F)c(-c2ccc(Cl)cc2)nc(C=O)c1Cl

Procedure:
In a typical reaction, 4-((3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone is treated with a 1 M (molar) solution of sulfuric acid in a mixture of acetonitrile/water. The mixture is heated at reflux until the reaction is complete. The mixture is added to methylene chloride, and the organic layer is separated, washed with brine and dried. The solvent is evaporated to provide crude 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde.