Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]([F:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20]([C@@:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])#[CH:21].CN(C)C(=N)N(C)C>CN(C=O)C.CC(=O)OCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:19][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:2]([C:21]#[C:20][C@@:22]2([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(F)cc(NC(=O)C(F)(F)F)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(NC(=O)C(F)(F)F)c1C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 51.8 %

Procedure:
A mixture of methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80 mmol), (PPh3)2PdCl2 (2.8 g, 4 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol), copper(I) iodide (764 mg, 4 mmol) and tetramethylguanidine (27.6 g, 240 mmol) in DMF (200 mL) was heated at 80° C. with nitrogen protection system for 16 hours. The cooled reaction mixture was diluted with EA (3×200 mL) and water (800 mL). The organic layer was separated, washed with water (2×200 mL), dried (Na2SO4), and concentrated. The remaining residue was chromatographed on silica gel, eluted with gradient 0-30% EtOAc in hexane to give the product (R)-benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (21 g, 53%) as white solid. 1H NMR (DMSO-d1) δ 11.01 (s, 1H), 7.64-7.77 (m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H), 3.85 (s, 3H), 3.44-3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), and 1.69 (s, 3H). MS (ESI) m/e [M+1]+ 507.0.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[K+]>CS(C)=O.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a solution of 4-nitro aniline (2 g, 14.48 mmol) and 2-bromo pyridine (3.43 g, 21.72 mmol) in DMSO (12 ml) was added powdered potassium hydroxide (3.24 g, 57.92 mmol) at room temperature and the reaction mixture was heated at 100° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, and water added. The organic layer was separated, washed with brine, dried and evaporated to give crude material. Purification by column chromatography using hexane/ethyl acetate (96:4) yielded (4-nitro-phenyl)-pyridin-2-yl-amine (0.28 g, 9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]3[CH2:28][O:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30]>CCO.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:27])[CH2:28][N:40]3[CH2:39][CH2:38][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])[CH2:42][CH2:41]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Temperature: 80 °C
Yield: 83.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.33 g, 13.2 mmol) and 1-(2-cyanophenyl)-piperazine (2.97 g, 15.86 mmol) were partially dissolved in EtOH (50 mL) and triethylamine (2 mL). The reaction mixture was heated to 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to give 3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (6.51 g, 83%) as a yellow solid. TLC (silica, 20% acetone/CH2Cl2): Rf=0.35. MS (electrospray): m/z 591.3 (591.3, calculated for C32H39ClN6O3, [M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:62]([O-:64])=[O:63].[Na+]>>[CH2:22]([O:21][N:16]1[C:17]([CH3:20])([CH3:19])[CH2:18][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:42][C:41]([CH3:43])([CH3:44])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:54])([CH3:55])[CH2:38]3)[N:3]=[C:2]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:62]([OH:64])=[O:63])[N:7]=2)[CH2:14][C:15]1([CH3:30])[CH3:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCCCCC(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound, a colorless glass, is prepared from 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and sodium 6-aminohexanoate according to the procedure of Example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH3:51])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH3:51])=[N:49][N:50]=2)=[O:43])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nnc(N)s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C)s4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methyl-1,3,4-thiadiazole (49 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 58 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][C@H:44]1[CH:49]2[CH2:50][CH2:51][N:46]([CH2:47][CH2:48]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:46]12[CH2:51][CH2:50][CH:49]([CH2:48][CH2:47]1)[C@H:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)s3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc(Cl)s3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (110 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (135 mg, 0.49 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-chloro-thiophen-2-yl)benzoxazole-4-carboxamide (22 mg, 17%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=7.3 Hz, 1H), 8.17 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.1 Hz, 1H), 7.69 (dd, J=8.2, 1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.06 (d, J=4.0 Hz, 1H), 4.50-4.45 (m, 1H), 3.65-3.60 (m, 1H), 3.30-3.20 (m, 2H), 3.15-3.05 (m, 2H), 3.02-2.95 (m, 1H), 2.30-2.55 (m, 2H), 1.95-1.78 (m, 3H); MS (ESI+) m/z 388 (M+H); HPLC>99% (AUC), tR=12.59 min.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC=C(C)C=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[C:5]([CH3:24])[CH:4]=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1cccc(N)c1
Solvent: CC(=O)O
Product: Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 15 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), m-toluidine (175 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 40 mg (0.13 mmol, 15% yield) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.O[Li].O>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)#[N:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (150 mg, 0.32 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (3.2 ml) and treated with LiOH.H2O (20 mg, 0.48 mmol). After 2 hours of stirring at 50° C., the solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Cyano-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (114.3 mg, 78% yield) as pale green foam. 1H NMR (DMSO-d6, 400 MHz): 7.80 (m, 2H), 7.45 (m, 4H), 4.44 (m, 1H), 3.35 (m, 2H), 3.13 (m, 2H), 1.96 (t, 1H), 1.88 (d, 1H), 1.75 (m, 1H), 1.70-1.40 (m, 6H), 1.20 (m, 3H), 0.70 (d, 3H), 0.60 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][OH:6])[OH:4].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:2]([CH:3]([CH2:5][OH:6])[OH:4])=[O:1])=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=CC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(=O)C(O)CO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 3.6 g. of glyceraldehyde and 2.44 g. of 4-dimethylaminopyridine in an ice-bath is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. After 4 hours at room temperature, chloroform and water are added. The chloroform extract is chromatographed quickly and evaporated in vacuo to yield 4-(n-hexadecylamino)benzoyl glyceraldehyde.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[N+:13]([C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22]([N+]([O-])=O)=[CH:23][CH:24]=3)[CH:19]([CH:32]3[O:36][CH2:35][CH2:34][O:33]3)[C:18]=2[CH:17]=1)([O-:15])=[O:14].CN(C)C=O>C(Cl)Cl>[SH:10][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[C:18](=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:28][CH:27]=3)[CH:19]([CH:32]3[O:36][CH2:35][CH2:34][O:33]3)[C:20]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc(S)ccc1-2
Reaction time: 0.5 h

Procedure:
For a period of 0.5 hours, 10 parts of sodium sulfide nonahydrate was added to a solution of 6 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane in 300 parts of dimethylformamide contained within a 1 liter flask at room temperature. The mixture was then stirred for 20 hours, diluted with 1000 parts of methylene chloride, and washed with water in the amount of 4 parts water: 1000 parts methylene chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[C:22]([Cl:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[ClH:30].[C:22]([NH:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccccc3)CCN1CC2
Product: Cl
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (5 g, 0.019 mole), 150 ml of benzene and 25 ml of 20% NaOH was cooled in an ice bath, and a solution of benzoyl chloride (2.7 g, 0.019 mole) in 10 ml of benzene was added dropwise with stirring. The mixture was stirred in the cold for 30 minutes and at room temperature for 1 hour. The solid was collected, dissolved in chloroform, washed with water, dried over MgSO4 and concentrated in vacuo to leave a solid residue. The solid was crystallized from acetone-petroleum ether and chromatographed over silica gel using benzene-MeOH (9:1) as the eluant. The major fraction (3.9 g) was converted to the HCl salt with hydrogen chloride in 2-propanol, and concentrated in vacuo to isolate the salt. The salt was crystallized from methanol-ether and again from absolute ethanol-ether to yield 3.0 g of the desired product, m.p. (decomposed at 250°-1°). This compound conforms with Formula II where R1 and R2 are OCH3, R3 is H and R4 is phenyl.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Cl[CH2:34][CH2:35][OH:36]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][CH2:35][OH:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: OCCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCO)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:30]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccccc3)CC2)nc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) in DMF (8 ml) was added benzoyl chloride (124 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylate.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([C:22](Cl)=[N:23][OH:24])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27]=[C:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:29]([O:31][CH3:32])=[O:30].C1COCC1>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([C:22]2[CH2:27][C:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])([C:29]([O:31][CH3:32])=[O:30])[O:24][N:23]=2)[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Cc1ccc(OCc2ccccc2)cc1C(Cl)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC1(C(=O)OC)CC(c2cc(OCc3ccccc3)ccc2C)=NO1
Reaction time: 2 h

Procedure:
Triethylamine (3.06 mL) was added to a mixture of 5-(benzyloxy)-N-hydroxy-2-methylbenzenecarboximidoyl chloride (6.05 g), dimethyl 2-methylenesuccinate (3.09 mL), and THF (100 mL) at room temperature, and the obtained mixture was stirred at 70 C for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.80 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1.C(O)(=[O:28])C>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:6](=[O:28])[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chromic oxide (IV) (0.41 g) was added to a solution of 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylnitrobenzene (0.3 g) in acetic acid (10 ml) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was extracted with ethyl acetate and washed with water, a saturated sodium bicarbonate solution and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (0.3 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C1(C)C=CC=CC=1.C[Al](C)C.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:30]([C:31](OCC)=[O:32])=[N:29][N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[C:27](=[O:43])[C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>ClCCl.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:30]([C:31]([N:3]([CH3:4])[CH3:2])=[O:32])=[N:29][N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[C:27](=[O:43])[C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1
Reactant: CNC
Reactant: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
0.815 g (10 mmol) of dimethylamine hydrochloride is introduced into 100 ml of toluene under argon, the solution is cooled to 0° C. and then 5 ml (10 mmol) of a trimethylaluminium solution (2M in toluene) are added in small portions. After stirring for 2 h at room temperature, 0.8 g (1.92 mmol) of ethyl 7-chloro-3-(3-chlorophenyl)-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate is added and the mixture is heated at reflux for 5 h. The solution is cooled to approximately 0° C. and the metal complex is slowly hydrolysed with water. 100 ml of dichloromethane are added and the solution is filtered. The precipitate is rinsed with dichloromethane, and 100 ml of water and 10 ml of a 1 M aqueous hydrochloric acid solution are added to the filtrate. The organic phase is separated by settling, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a silica column (eluant: dichloromethane/ethyl acetate: 80/20). After recrystallizing from ethyl acetate, 0.43 g (1.0 mmol) of compound is isolated in the form of a white solid.