Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>C(O)(C)(C)C>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Yield: 73.2 %

Procedure:
A preparation of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione (378 mg, 1.02 mmol) was heated to 50° C. in tert-butanol (10 ml) and potassium t-butoxide (11 mg, 98 μmol) for 16 hours. The mixture was poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione as a tan powder (276 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 11.03 (s, 1H), 7.32-7.4 (m, 4H), 7.17 (d, 1H, J=7.2 Hz), 7.07 (t, 1H, J=7.6 Hz), 6.96 (t, 1H, J=7.6 Hz), 6.82-6.89 (m, 2H), 4.5 (dd, 2H, J=7.2 and 20 Hz), 4.07 (t, 2H, J=5.2 Hz), 2.87 (t, 2H, J=6 Hz), 2.08 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[Cl:31].[OH-].[Na+].C(Cl)(Cl)Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:30][C:27]3[CH:28]=[CH:29][C:24]([NH2:23])=[C:25]([Cl:31])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc(N)c(Cl)c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (30.0 g) and tetrabutylammonium chloride (13.9 g) were dissolved in acetone (400 ml), and the solution was stirred at room temperature. A solution of 4-amino-3-chlorophenol hydrochloride (36.0 g) in a 20% aqueous sodium hydroxide solution (64 ml) was added thereto. The mixture was then heated under reflux for 3 hr. The reaction solution was cooled to room temperature, and chloroform and water were added to the cooled reaction solution, followed by extraction with chloroform. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. Next, sodium sulfate was removed, and the solvent was then removed by distillation. The residue was washed with methanol, and the washed solid was subjected to evaporation to dryness in vacuo through a vacuum pump to give 36.6 g (yield 90%) of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=2[O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)[CH:12]=[CH:13][CH:14]=1.CI>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=2[O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:1])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.5 %

Procedure:
130 mg of potassium carbonate were added to a solution of 500 mg of (S)-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in Example 57(b)] in 5 ml of dimethylacetamide, and the resulting mixture was stirred at room temperature for 5 minutes, after which 288 mg of methyl iodide were added. The reaction mixture was then stirred at room temperature for 5 minutes, after which it was diluted with ethyl acetate. The diluted solution was then washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 320 mg (yield 61%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[NH:22][CH2:21][C:20](=[O:23])[N:19]1[CH2:24][C:25]([NH2:27])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:13])[C:14]([N:22]1[CH2:21][C:20](=[O:23])[N:19]([CH2:24][C:25]([NH2:27])=[O:26])[C:18]1([CH3:28])[CH3:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)N(CC(N)=O)C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice cold solution of N-(benzyloxycarbonyl)alanine (6.7 g) and 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (5.2 g) in 100 ml of dimethylformamide (DMF), a solution of dicyclohexylcarbodiimide (DCC) (6.2 g) in 50 ml of DMF was added dropwise during 15'. The suspension was stirred at 0° C. for 2 hours and at room temperature for additional 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, affording crude 3-[2-(benzyloxycarbonylamino)propionyl]-2,2-dimethyl-5-oxo-1-imidazolidineacetamide m.p. 206°-210° C. Into a solution of this compound (3 g) in methanol (100 ml) containing 5% palladium on charcoal (0.6 g) hydrogen was bubbled at 20° C. for 1.5 hours. Removal of catalyst and evaporation of the solvent gave a residue which was triturated with ethanol to afford the title compound, m.p. 196°-197° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28][NH:29]C(=O)C)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:33])([CH3:3])[CH3:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28][NH:29][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:33])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CNS(C)(=O)=O)ccc21

Procedure:
N-[2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-methanesulfonamide was prepared by the same procedure as N-[2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-acetamide, except using methanesulfonyl chloride.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][N:2]1C(OCC)=O.[ClH:15]>>[ClH:15].[ClH:15].[CH2:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][NH:2]1
Reactant: CCOC(=O)N1Cc2ccncc2C1
Agent: Cl
Product: c1cc2c(cn1)CNC2

Procedure:
10.4 g (51 mmol) of ethyl 2,3-dihydro-1H-pyrrolo-[3,4-c]pyridine-2-carboxylate are refluxed for 15 hours together with 100 ml of concentrated hydrochloric acid. The batch is evaporated, and the crystalline residue is stirred with acetone. The product is filtered off with suction and dried in the air.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylsulfonylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound: Rf=0.31 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: N#CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1CCN(C(=O)CCl)CC1
Temperature: -10 °C
Yield: 92.9 %

Procedure:
A mixture of 4-piperidinecarbonitrile (200 g, 1.80 mol) and 40% aqueous potassium carbonate solution (342 g, 0.99 mol) in dichloromethane (1 L) was cooled to −10° C., and a solution of chloroacetyl chloride (210 g, 1.86 mol) in dichloromethane (300 mL) was added over about 75 minutes while maintaining the reaction mixture at −10 to 0° C. After the addition was complete, the reaction mixture was separated, the upper aqueous phase was extracted with dichloromethane (2×300 mL), and the combined organic phases were concentrated under reduced pressure to give 312 g of the title compound as a liquid which slowly crystallized on standing. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:24]([OH:26])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28].Cl>C(O)C>[CH2:27]([O:25][C:24](=[O:26])[C@H:17]([CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)[NH:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:28]
Reactant: O=C(CCNC(=O)OCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CCNC(=O)OCc1ccccc1

Procedure:
A 1 L round-bottom flask, under nitrogen atmosphere, is loaded with 40 g of 3-(benzyloxycarbonylamino) propionyl-L-histidine, 200 g of absolute ethanol and 80 g of an 8M HCl ethanol solution.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11](C(=O)C2C=CC=C(C=O)C=2)[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([OH:33])[CH3:32]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][CH:5]=[C:32]([CH2:31][OH:33])[CH:29]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)N(C(=O)c2cccc(C=O)c2)c2ccccc2N)cc1
Reactant: CCO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(CO)c2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 57, N2-(4-tert-butylbenzoyl)-N2-(3-formylbenzoyl)-1,2-benzenediamine (230 mg, 0.57 mmol) was reacted in ethanol to yield 227 mg (99%) of the title compound as an off-white amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1[C:16]2[NH:17][CH:18]=[CH:19][C:15]=2[C:14]([N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[N:13][CH:12]=1.CN1CCOCC1>ClCCl.CN(C=O)C>[C:1]1([CH2:7][C:8]([NH:26][CH:23]2[CH2:22][CH2:21][N:20]([C:14]3[C:15]4[CH:19]=[CH:18][NH:17][C:16]=4[N:11]=[CH:12][N:13]=3)[CH2:25][CH2:24]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Cc1ccccc1)NC1CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 8 h

Procedure:
Phenylacetyl chloride (0.037 g, 0.240 mmol, commercially available from e.g sigma-aldrich or fluka) in Dichloromethane (DCM) (1.5 ml) was added to a solution of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (0.043 g) and POL-NMM (0.279 g, 0.600 mmol) in DMF (1.5 ml). The mixture was shaked overnight at room temperature on a mini block. The resulting mixture was washed using DCM DMF (1:1) and the acid chloride left was removed using an NH2 cartridge. Then the solvents were evaporated overnight using the genevac. The crude was finally purified via MDAP using a formic acid method to obtain the desired product E51 in 24 mg. LCMS [M+H]+336.06@0.62 min (2 min run)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].N[C:37](N)=[O:38]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:35][C:37](=[O:38])[N:8]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1
Reactant: NC(N)=O
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Product: O=c1[nH]c2c(Cl)ncnc2n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 49.9 %

Procedure:
7.5 Parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine and 3.6 parts of urea were heated together till about 220° C. during 10 minutes. The resulting melt was cooled and suspended in water. The solid was filtered off, washed with water and ethanol and recrystallized from a mixture of N,N-dimethylacetamide, ethanol and water, yielding 3.9 parts (49.9%) of 6-chloro-9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-7.9-dihydro-8H-purin-8-one; mp. 266.2° C. (compound 144).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>ClCCl>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Cl)c1
Yield: 73.9 %

Procedure:
A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g of N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is washed with saturated NaHCO3 solution and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82-83° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0525 g, 0.107 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylmethyl)benzofuran-3(2H)-one (0.0384 g, 92%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15].FC1C=CC(O)=C(F)C=1F>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: Oc1ccc(F)c(F)c1F
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
We have studied the method of the U.S. Pat. No. 2,439,237 to determine whether or not it can be applied to 3,4,5,6-tetrafluorophthalic acid which is the starting material for the present invention. As indicated in a comparative experiment (control), 3,4,5,6-tetrafluorophthalic acid was simply heated in an alkaline aqueous solution in accordance with the method of the U.S. Patent for the purpose of decarbonating the acid. The reaction which ensued mainly gave rise to trifluorophenol having fluorine atoms substituted by hydroxyl groups and failed to produce 2,3,4,5-tetrafluorobenzoic acid selectively. It may be safely concluded that the fluorine atom at the para position of a benzene ring posessing such an electron-attracting group as the --COOH group is more susceptible to the nucleophilic substitution reaction than the chlorine atom at the same position. By the method of the U.S. Pat. No. 2,439,237, therefore, the alkaline substance is believed to form a phenol by substitution of the fluorine atom. It is, accordingly, proper to conclude that the method, when applied to 3,4,5,6-tetrafluorophthalic acid, is liable to induce secondary reactions and is not useful for the decarboxylation aimed at by the present invention. Methods for the decarboxylation of 3,4,5,6-tetrafluorophthalic acid are described in G. G. Yacobson et al, Journal of General Chemistry, 36, No. 1,144 (1966) and British Pat. No. 2,122,190. The former method causes this acid to react in dimethylformamide as a solvent at a temperature of 145° C. This method, however, dose not deserve commercialization because it produce 2,3,4,5-tetrafluorobenzoic acid in low a yield of 44.0 mol %. The latter method causes the acid to react in an organic solvent, and that at a temperature of 200° C. It does not produce any 2,3,4,5-tetrafluorobenzoic acid but barely gives rise to 1,2,3,4,-tetrafluorobenzene in a yield of 0.5%.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22](N)=[O:23]>C(O)=O>[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]([CH:22]=[O:23])[CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC=O
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2
Agent: Cl
Solvent: O=CO
Product: COc1ccc2c(c1OCc1ccccc1)CCN(C=O)C2
Temperature: 0 °C

Procedure:
122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline-hydrochloride, 140 ml of formic acid, and 700 ml of formamide are heated for 2.5 hours under reflux. The mixture is then poured over 2 kg of ice and extracted with methylene chloride. After evaporation to dryness of the methylene chloride solution under reduced pressure, the residue is recrystallized from methanol-water. 102.3 g of 5-benzyloxy-2-formyl-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are obtained. m.p. = 117.5° - 118.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH2:16]([C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:21]=[C:20]([CH2:32][CH3:33])[C:19]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]O)[CH:35]=1)[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:40][C:36]3[CH:35]=[C:34]([C:19]4[C:18]([CH2:16][CH3:17])=[CH:23][C:22]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:21][C:20]=4[CH2:32][CH3:33])[CH:39]=[CH:38][CH:37]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.377 g, 1.00 mmol) and tributylphosphine (0.399 mL, 1.60 mmol) in toluene (16 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 2 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.526 g, yield 93%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1Cl
Yield: 46 %

Procedure:
The title compound is prepared from 3-amino-4-chloro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=1.28 min; Mass spectrum (ESI+): m/z=341/343 (Cl) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11]C[O:9]2)=[CH:4][N:3]=1>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:9][CH2:11][CH2:12][O:13]2)=[CH:4][N:3]=1
Reactant: Brc1ccc(C2OCCCO2)cn1
Solvent: OCCO
Product: Brc1ccc(C2OCCO2)cn1
Yield: 61 %

Procedure:
Following the procedure described above for the synthesis of compound 28 (Scheme 8) but substituting 1,3-propanediol (27) for 1,2-ethanediol (34), title compound 35 was obtained in 61% yield [Romero-Salguero, F. J.; Lehn, J-M.; Tetrahedron Letters, 40, 1999, 859-862]. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45 (d, J=2.3 Hz, 1H), 7.79 (ddd, J=8.2, 2.5, 0.4 Hz, 1H), 7.69 (dd, J=8.2, 0.8 Hz, 1H), 5.83 (s, 1H), 4.10-3.93 (m, 4H). MS (m/z): 230.0 (M+H).