Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP(N)(=O)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[C:17]=23)=[CH:9][C:8]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(C)C.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:63]=2)C=CC=1OCC1C=CC(OC)=CC=1)C1C=CC=CC=1.O=P(Cl)(Cl)Cl>>[NH2:63][C:18]1[C:17]2[N:16]([C:15]([CH:23]3[CH2:24][CH2:25][CH2:26]3)=[N:14][C:13]=2[C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:9]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)OP(N)(=O)Oc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Reactant: COc1ccc(COc2ccc(C(NC(=O)C3CCC3)c3nccnc3Cl)cc2OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(O)c(OCc4ccccc4)c3)c12

Procedure:
Phosphoramidic acid 2-benzyloxy-4-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-phenyl ester isopropyl ester: Followed General Cyclization described in Example 92-(a) whereby Cyclobutanecarboxylic acid [[3-benzyloxy-4-(4-methoxybenzyloxy)-phenyl]-(3-chloropyrazin-2-yl)-methyl]-amide was treated with POCl3 and then quenched with 2N NH3 in iPrOH to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 1.31 (d, 3H, J=6.0 Hz), 1.35 (d, 3H, J=6.4 Hz), 2.01-2.26 (m, 2H), 2.47-2.69 (m, 4H), 3.02 (d, 2H, J=4.0 Hz), 3.84 (quintet, 1H, J=8.4 Hz), 4.78 (septet, 1H, J=6.1 Hz), 5.17 (s, 2H), 7.27-7.53 (m, 10H); MS (ES): 526.9/528.9 (M/M+2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:50]=[C:51]([N:55]2[CH2:59][CH2:58][CH:57]([C:60](O)=[O:61])[C:56]2=[O:63])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:60]([CH:57]1[CH2:58][CH2:59][N:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([F:48])[CH:50]=2)[C:56]1=[O:63])=[O:61]
Reactant: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(F)c2)C1=O
Yield: 41.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.350 g; 0.672 mmol), N,N-diisoprpylethylamine (0.232 mL; 1.34 mmol) and 1-(3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (41%) of the title compound as a white solid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:11]\[CH3:12])/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:11](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:12]
Reactant: C/C=C(/C=C/C(=O)OCC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C=C(/C=C/C(=O)O)CC
Yield: 97.1 %

Procedure:
To a solution of 20.0 kg (119 mol) of ethyl (E,E)-4-ethyl-2,4-hexadienoate in 15 l of methanol is added a solution of 6.0 kg (150 mol) of sodium hydroxide in 60 l of water. The mixture is heated at 50°-55° C. for 1 hour and then cooled to 20°~25° C., poured into a 8%-hydrochloric acid solution at same temperature. The precipitate formed is collected by filtration, washed with 200 l of water and dried in vacuo overnight to give 16.2 kg of (E,E)-4-ethyl-2,4-hexadienoic acid (Yield 97.4%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]=1[N+:35]([O-])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:35][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH3:25])[C:30]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:31]
Reactant: Cc1nccn1-c1ccc(N)cc1C(F)(F)F
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (1.0 g, 4.15 mmol), triethylamine (1.74 mL, 12.5 mmol) in anhydrous CH2Cl2 (60 mL) at 0° C. is added 4-methyl-3-nitro-benzoyl chloride (660 μL, 4.57 mmol) dropwise. After stirring for 2 hours at room temperature, the reaction mixture is poured into 100 mL CH2Cl2 and 50 mL saturated NaHCO3 solution with rapid stirring. After 10 minutes, the mixture is partitioned in a separator funnel and extracted three times with 100 mL CH2Cl2. The organic extracts are washed with brine, and dried over MgSO4. Filtration and concentration under reduced pressure, afforded the desired compound, which is used in the next step without any further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](Cl)[CH:10]=1>CN1C(=O)CCC1.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH2:8])=[CH:10][C:11]=1[O:7][CH2:6][CH2:5][O:4][CH3:3])#[N:14]
Reactant: COCCO
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCOc1cc(N)ccc1C#N
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
Sodium hydride (300 mg of an 80% suspension in mineral oil, 10 mmol) was added to 2-methoxyethanol (0.76 g, 10 mmol) in NMP (5 ml) and the mixture stirred for 15 minutes. 4-Amino-2-chlorobenzonitrile (1.5 g, 10 mmol) was added and the mixture heated at 100° C. for 5 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with increasingly polar mixtures of methylene chloride/ethyl acetate to give 4-cyano-3-(2-methoxyethoxy)aniline (760 mg, 40%) as a dark yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][C:3]=12.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[C:10]([CH:28]=[O:29])[C:3]=12
Reactant: O=C(O)C(F)(F)F
Reactant: COCCCn1ccc2c(F)ccnc21
Agent: C1N2CN3CN1CN(C2)C3
Product: COCCCn1cc(C=O)c2c(F)ccnc21

Procedure:
A solution of 4-fluoro-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridine (520 mg) and hexamethylenetetramine (700 mg) in trifluoroacetic acid (9.1 ml) was stirred at 80° C. for 4 hours. After evaporation of the solvent in vacuo, the resulted residue was dissolve in ethyl acetate. The solution was poured slowly into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=60/40 to 20/80) to give 4-fluoro-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (260 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl.O1CCOCC1.[Na]>O>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC2CC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 120 °C
Yield: 77.6 %

Procedure:
10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (75 mg, 0.37 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (120 mg, 0.41 mmol) and 4N HCl in dioxane (275 μl, 0.41 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil (87 mg). The crude reaction was purified on a 80 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (133 mg, 78%) as a beige powder. MP: 220° dec.; 1H-NMR (CDCl3) δ 10.97 (s, 1H), 8.66 (d, J=8.3, 1H), 8.09 (s, 1H), 7.50-7.38 (m, 3H), 7.21 (d, J=5 Hz, 1H), 7.08 (m, 2H), 6.91 (s, 1H), 6.20 (br s, 1H), 3.12-2.95 (m, 5H), 2.87 (br, s), 2.45-2.20 (m, 6H), 1.69 (d, J=10.1 Hz, 2H), 0.90 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].S(OC)(O[CH3:27])(=O)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[O:16][CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of 3.9 g (0.081 mole) of 50% sodium hydride/mineral oil in 85 ml of N,N-dimethylformamide under a nitrogen atmosphere was cooled in ice and treated portionwise over 90 minutes with 17.1 g (0.064 mole) of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)]. The mixture was stirred in ice an additional one hour, 7.9 ml (10.5 g; 0.083 mole) of dimethyl sulfate was added dropwise over 15 minutes, the ice bath was removed, and stirring was continued for a total of 65 hours. The reaction mixture was added to 600 g of ice/water, acidified with 4.0N hydrochloric acid, and extracted with dichloromethane (4×250 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous sodium sulfate), and evaporated to yield a crude residue of 3-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, plus a small amount of N,N-dimethylformamide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+]>>[OH:15][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C1CCCO1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(CCCO)CC(=O)c1ccccc1

Procedure:
60.0 g of acetophenone, 47.4 g of butyrolactone and 99.0 g of sodium methylate (30% solution in methanol) are reacted in the same manner as described in Example 8. After working up as described in Example 8, the product precipitates from the mother solution after several hours. The precipitate is isolated by filtration, washed with water and dried to constant weight under vacuum at ca. 30° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH2:19][CH2:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=Cc1ccccn1
Reactant: COc1cc2c3c(c1)c1cc(Br)ccc1n3CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
10-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (0.7 g) obtained in Example 1, step 3 was suspended in ethanol (30 ml), and pyridine-2-aldehyde (0.7 g) and sodium hydroxide (0.3 g) dissolved in water (5 ml) were added at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The precipitated crystals were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (0.56 g, 61%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:30][C:31]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:32]=1[CH2:33]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:31]=2[F:30])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2[N:14]=1.[ClH:20]>C(#N)C.[Cu](Cl)Cl>[Cl:20][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2[N:14]=1
Reactant: Cl
Reactant: Cc1cccc2sc(N)nc12
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1cccc2sc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution containing copper chloride (II) (1.96 g, 14.61 mmol) and tri(ethylene glycol) dimethyl ether (6 mL) in acetonitrile (100 mL) was added isoamyl nitrite (2.14 g, 18.27 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 2-amino-4-methylbenzothiazole (2.0 g, 12.18 mmol) in tri(ethylene glycol) dimethyl ether (10 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (400 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water, brine, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane to afford 2-chloro-4-methyl-1,3-benzothiazole (1.6 g, 71%). 1H NMR (400 MHz, CD2Cl2) δ 2.70 (s, 3H), 7.32 (m, 2H), 7.64 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C)c1C
Reaction time: 36 h

Procedure:
To a solution of 2,3-dimethylphenol (25.0 g, 205 mmol) in dimethylsulfoxide (200 mL) were added ethyl 2-bromo-isobutyrate (60 mL, 409 mmol) and potassium carbonate (56.5 g, 409 mmol) at room temperature, and the mixture was stirred for 36 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude oily ethyl 2-(2,3-dimethylphenoxy)-2-methylpropionate. 12 N Aqueous sodium hydroxide solution (20 mL, 240 mmol) was added to the mixed solution of this compound in THF (160 mL) and methanol (40 mL) at room temperature, stirred for 12 hours, and then concentrated under reduced pressure. Water and hydrochloric acid were added to the reaction solution to acidity the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized from ethyl acetate-hexane to obtain 21.3 g (yield 50%) of the title compound. Melting point: 71-73° C.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[C].[Pd]>[CH3:22][C@@H:10]1[CH2:9][NH:8][C@@H:13]([CH3:14])[CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
Under an argon atmosphere, (2R,5S)-tert-butyl 4-benzyl-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 6.57 mmol) was dissolved in methanol (60 mL), and added 10% palladium carbon (670 mg) and formic acid (1.5 g, 32.9 mmol). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was added chloroform and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over sodium sulfate, concentrated in vacuo, and the title compound (1.56 g, >100%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:29])[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:29])[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: COc1ccc(N)c(=O)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c(=O)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (0.36 g) and 2-amino-5-methoxy-2,4,6-cycloheptatrien-1-one (0.20 g) in xylene (9 ml) was refluxed for 40 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and washed with xylene to give 4-hydroxy-N-(5-methoxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.45 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([O:20]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[CH:27]=[CH:26][N:25]=[CH:24]1.C[O-].[Na+].C1(C)C=CC=CC=1>CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:40][C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][CH2:29][CH2:28][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH:32]=[CH:33]2)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Reactant: Nc1ccc2c(ccn2CCCn2ccnc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(Nc1ccc2c(ccn2CCCn2ccnc2)c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A mixture of 27.9 g of ethyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate, 17.8 g of 1-[3-(imidazol-1-yl)propyl]-5-aminoindole, 8 g of sodium methylate and 600 ml of toluene was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, the crystals being separated were collected by filtration and washed with toluene. Thus obtained crystals were dissolved in 500 ml of chloroform, then 100 ml of water was added and the mixture was filtrated with Celite. The chloroform layer was taken by separation, after washed with water, the chloroform portion layer was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation to obtain brown oily product. This oily product was dissolved in methanol, further added n-hexane and the crystals being separated were collected by filtration, recrystallized from methanol and dried. There was obtained 31.8 g of 1-benzyl-6-chloro-2-{1-[3-(imidazol-1-yl)propyl]indol-5-ylamino-carbonyl}benzimidazole.
Reaction SMILES: CN(C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:12][O:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:3][O:4][C:18]=1[CH:17]=[O:16]
Reactant: CN(C)C=O
Reactant: COc1ccoc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccoc1C=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
A 3-L, one-necked, round-bottomed flask was equipped with a Teflon-coated magnetic stirbar. The system was flame-dried and flushed with argon. The flask was charged with a solution of N,N-dimethylformamide (31.9 mL, 413 mmol, 1.35 equiv) in dichloromethane (1.2 L). The solution was cooled to 0° C. in a dry ice-acetone bath, and then oxalyl chloride (32.5 mL, 367 mmol, 1.2 equiv) was added over 16 min. Vigorous bubbling occurred and a white solid precipitated. After stirring for 20 min, the reaction mixture was cooled to −40° C. by addition of dry ice to the cooling bath and a solution of 3-methoxyfuran (Meister, C.; Scharf, H.-D. Synthesis 1981, 737-739) (30 g, 306 mmol, 1 equiv) in dichloromethane (100 mL) was added via cannula. A dark-brown color formed during the addition. After stirring for 20 min, the cooling bath was removed and saturated aqueous sodium bicarbonate solution (1.5 L) was added. The biphasic mixture was stirred vigorously for 6 hours, and then was partitioned. The aqueous layer was further extracted with dichloromethane (2×800 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (100% diethyl ether) to furnish 3-methoxyfurfural 6 (21.2 g, 55%) as a light-yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>CO>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:3](=[O:2])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCNC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (75 mL) was treated with N,N-dimethylethylenediamine (0.2 mL) and the mixture was refluxed for 18 hours. The solvents were removed by evaporation and the residue was purified by HPLC (ethyl acetate-methanol-triethylamine; 95:5:2) followed by crystallization from ethyl acetate-hexane to give 0.28 g of N-[2-(dimethylamino)ethyl]-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 102°-104° C.