Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[C:17]#[C:18][C:19]2[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[CH:6][C:5]=1[F:26].[OH-].[Na+]>C1COCC1>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([C:18]#[C:17][C:11]2[C:12]([CH3:16])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([F:26])[CH:6]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(-c2ccnc(C)c2C#Cc2ccc(N)nc2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 300 mg (0.83 mmol) 4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester using 0.83 mL (0.83 mmoL) 1 N NaOH in 5 mL THF. The precipitate is collected by filtration and washed with THF. Yield: 280 mg (97%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([CH3:11])=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CCO.O>[CH:1]1([N:6]2[C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1C1CCCC1
Yield: 64 %

Procedure:
A solution of ethyl 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylate (15.5 g, 70 mmol) in EtOH (200 mL) was treated with a solution of LiOH (6 g, 250 mmol) in water (100 mL) and the resultant mixture was stirred at 60° C. overnight. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was acidified with aq HCl (2 M) to pH 3 and was extracted with EtOAc. The extract was concentrated under reduced pressure to give 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylic acid (8.7 g, 64% yield). 1H NMR (300 MHz, DMSO-d6): δ 12.05 (br s, 1 H), 8.10 (s, 1 H), 4.60 (m, 1 H), 2.28 (s, 3 H, 2.04-1.97 (m, 2 H), 1.89-1.85 (m, 2H), 1.78-1.71 (m, 2 H), 1.62-1.59 (m, 2 H); MS (ESI) m/z: 194.99 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].[H-].[Na+].CCO>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 174.1 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (1.0 g) and 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.3 g) in DMF (10 mL) was added 60% NaH (0.23 g) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. To the mixture was added EtOH (10 mL). The formed crystals were collected by filtration and washed with EtOH. This microwave reaction was repeated two additional times with the same amount of starting material. The combined crystals were recrystallized from EtOH containing 5% distilled water (270 mL) and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.3 g) as white crystals (Form A).
Reaction SMILES: CON(C)[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]([CH3:8])[CH3:7].C[Li].[CH3:21]C#N>C1COCC1.C(=O)=O.CCOC(C)=O.O>[CH3:8][CH:6]([C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:4](=[O:17])[CH3:21])[CH3:7]
Reactant: CC#N
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: O=C=O
Agent: [Li]C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-tert-butyl 1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (4.23 g, 16.25 mmol) in THF (100 mL) at −70° C. was added drop wise methyl lithium (1.071 g, 48.7 mmol). Cold bath was replaced with −40° C. bath (MeCN in dry ice) removed and the reaction was stirred for 4 hours. Saturated NH4Cl solution (10 mL) was then added cautiously to quench the reaction. The reaction mixture was then allowed to warm to room temperature, and diluted with EtOAc (100 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (3.01 g). LCMS m/z 238.2 (M+Na)+, Rt 0.78 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>O>[OH:22][CH2:21][CH2:20][N:19]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)[CH2:23][CH2:24][OH:25]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: OCCNCCO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(N(CCO)CCO)n1
Temperature: 0 °C
Yield: 74 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.1 ml (0.02 mol) of diethanolamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried. 1.9 g of yellow powder are obtained, ie a yield of 74%.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].Cl.[CH3:46][NH:47][CH2:48][CH2:49][Cl:50].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:50][CH2:49][CH2:48][N:47]([CH3:46])[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CNCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCl)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Yield: 86.6 %

Procedure:
A solution of 50 mg of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e, 9.3 mg of N-methyl-N-(2-chloroethyl)amine hydrochloride, 43 μL of diisopropylethylamine, and 35 mg of HATU in 1000 μL of DMF was stirred for 1 h. The mixture was diluted with 20 mL of water, and the resulting precipitate was collected by filtration. It was dissolved in dichloromethane and the solution was washed with water and dried (Na2SO4). The solvent was evaporated to give 42 mg of product.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]1[CH:26]=[CH:25][C:11]([C:12](OC2C=C(F)C(C#N)=C(F)C=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCC1C=CC(C(O)=O)=CC=1)CCCC.S(Cl)([Cl:45])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:6][CH2:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([Cl:45])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCc1ccc(C(=O)Oc2cc(F)c(C#N)c(F)c2)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCCOCc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCOCc1ccc(C(=O)Cl)cc1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4-(pentyloxymethyl)benzoate (in the formula (1), R=C5H11, l=1, m=1, n and o=both, 0; A1 =1,4- phenylene group, Z1 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 1)) 4-(Pentyloxymethyl)benzoic acid. (1.6 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(pentyloxymethyl)benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: C#CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 65 mg of 3-bromo-1-butyne were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 159 mg (yield, 92%) of 3-{2,4-dichloro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-371).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=O)[NH:9][C:5]=2[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][C:5]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Product: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1

Procedure:
Reflux 5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one (17 g; Meanwell et al. (1995) J. Org. Chem. 60(6):1565-1582) for 14 hours in POCl3 (200 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1 :1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethyl-1H-benzimidazole.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>CN(C=O)C>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOC(OCCN1C(=O)c2ccccc2C1=O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Benzil-di(β-bromoethyl)ketal (8.84 g) and 7.4 g of potassium phthalimide were dissolved in 50 ml of DMF, and reacted at 50° to 60° C. for 6 hours. When the reaction mixture was poured into 100 ml of ice water, white crystals formed. The crystals were collected by filtration, well washed with water, and dried to give 11 g of benzil-di-(β-phthalimidoethyl)ketal in a yield of 96%. Recrystallization from a mixture of ethanol and chloroform afforded crystals having a melting point of 132° to 134° C. The product is referred to as initiator 2.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1.[I:23]Cl>>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:16]=1[I:23]
Reactant: ClI
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: c1ccc2[nH]ccc2c1
Product: CCOC(=O)Cc1ccc(N)c(I)c1

Procedure:
Generally, Scheme 1 illustrates a synthetic route to the indole-containing fused ring compounds of the present invention. An ethyl 2-(4-aminophenyl)acetate is iodinated with a reagent such as, for example, iodine monochloride, to afford the corresponding ethyl 2-(4-amino-3-iodophenyl)acetate. This amine is treated with a 3-oxoacetate to produce the desired ethyl 3-(phenylamino)but-2-enoate. Formation of the indole is then achieved upon treatment with a catalyst, such as, for example, palladium acetate. The resulting ethyl 2-[3-(ethoxycarbonyl)indol-5-yl]acetate is saponified with a base such as potassium hydroxide to afford the 2-[3-(ethoxycarbonyl)indol-5-yl]acetic acid. The acid is subsequently converted to the amide by treatment with an amine and a suitable coupling agent, such as, for example, N,N′-carbonyldiimidazole or dicyclohexylcarbodiimide. Cyclization of the amide (e.g., in the presence of phosphorous oxychloride via the Bischler-Napieralske reaction) affords the dihydroisoquinoline, which is then treated with, for example, oxomethyl 2,2-dimethylpropanoate to produce the corresponding trihydroisoquinoline-2-carbaldehyde-ene. This compound is further cyclized and subsequently reduced to form the 6,11,12,13,12a,6a-hexahydroisoquinolino[2,1-b]pyrrolo[2,3-h]isoquinoline. The R4 group (as found in Formula I) can be present on the starting ethyl 2-(4-aminophenyl)acetate or introduced at various steps of the scheme (such as depicted in Scheme 1), depending on the nature of the group. The indole nitrogen can also be alkylated with various procedures known in the art.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(C)(=O)=O)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 23 mg (0.2 mmol) methyl sulfonyl chloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 45 mg (50%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-methanesulfonamide as a light yellow solid. MS ISP (m/e): 450.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.40 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.54 (d, 1H), 7.24 (d, 1H), 7.06 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 4.36 (q, 1H), 3.84 (s, 3H), 2.14 (s, 3H), 1.65 (m, 3H), 0.89 (m, 6H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[I-].[Na+].[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Reaction time: 13 h
Yield: 76.8 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (534 mg; 3.0 mmol) and sodium iodide (3.0 g; 20 mmol) were added to a solution in methanol (20 ml) of 4-(4-benzyl-1-piperazinyl)-aniline (1.1 g; 4.1 mmol) synthesized by the above process, and the mixture was stirred for 13 hours in a bath controlled at 70° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 775 mg of impurity-containing 4-(4-benzyl-1-piperazinyl)-1-(1piperazinyl)benzene as an oil. Trimethylamine (0.3 ml; 2.2 mmol) and di-tert-butyl dicarbonate (450 mg; 2.1 mmol) were added to a solution of this oil (775 mg) in methylene chloride (5 ml) under ice cooling, and the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining crude crystals (738 mg; yield: 42%) of 4-(4-benzyl-1-piperazinyl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-benzene. The crude crystals were recrystallized from chloroform-diethyl ether-n-hexane to obtain colorless flakes (melting point: 132-133° C.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu].C1(C)C=CC=CC=1>[C:8]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 129.3 %

Procedure:
That is, in a two-neck flask of 500 ml in volume, 152.0 g anhydrous sodium carbonate (1.10 mol) and 9.5 g powdery copper (0.15 mol) were added and then heated for 2 hours while stirring to uniform. Subsequently, after cooling to room temperature, the solution was added with 67.6 g of an aniline compound (0.5 mol) represented by the formula (49) described below and 305.9 g of iodobenzene (1.5 mol) and then heated again to 220° C. to allow the reaction for 2.5 hours. After that, the solution was cooled to room temperature and then added with 100 ml toluene, followed by filtration. The resulting residue was dissolved in toluene and dried over activated clay. After that, the residue was dissolved in toluene and then added with methanol to crystallization. Then, the residue was dissolved in toluene again and added with methanol to crystalline and the resulting residue was followed by filtration and dried to form crystal. Subsequently, the resulting crystal was purified through silica gel column chromatography (developing solvent: chloroform/hexane solvent), thereby obtaining 79.3 g of a triphenylamine derivative compound represented by the general formula (50) (yields: 55.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of methyl 2-amino-4-chlorobenzoate (20.0 g, 108 mmol) in DMF (200 mL) was added N-bromosuccinimide (19.2 g, 108 mmol) in one portion and stirred overnight at room temperature. The resulting solids were filtered off and dissolved in toluene, dried with Na2SO4, and concentrated to give methyl 2-amino-5-bromo-4-chlorobenzoate (26.47 g, 93%)
Reaction SMILES: Cl.O1CCOCC1.C(O[C:11](=[O:25])[CH2:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([CH3:24])[CH:18]=1)=[O:15])C>O1CCOCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:11](=[O:25])[CH2:12][NH:13][C:14]2=[O:15])=[CH:18][C:19]=1[CH3:24]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(Br)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N2C(=O)CNC2=O)ccc1Br
Temperature: 80 °C
Reaction time: 17 h
Yield: 55.4 %

Procedure:
4 N HCl-dioxane (7.5 ml, 30 mmol) was added to a solution of the crude product [3-(4-bromo-3-methyl-phenyl)-ureido]-acetic acid ethyl ester (5.07 g) in dioxane (60 ml), and the mixture was heated with stirring at 80° C. for 17 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and water was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-(4-bromo-3-methyl-phenyl)-imidazolidine-2,4-dione (2.40 g, 37%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[N:12]([CH3:27])[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]([O:22]C(C)(C)C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([S:7]([NH:10][C:11]2[N:12]([CH3:27])[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]([OH:22])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c2c(c(C(=O)OC(C)(C)C)c1NS(=O)(=O)c1ccccc1)CCCC2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c2c(c(C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
tert-Butyl 2-benzenesulphonylamino-1-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (Intermediate 21, 0.3 g) was added to HCl in dioxane (4M, 3.8 ml) at 0° C. The cold bath was removed and the mixture was allowed to warm to room temperature and then stirred for 2 hours. The mixture was cooled to 0° C. and neutralised with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with DCM (15 ml). The solid was collected by filtration and triturated with hot ethyl acetate (3 ml). The solid was collected by filtration and air dried to afford 2-benzenesulphonylamino-1-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (0.017 g) as a white solid.