Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0 g, 53.7 mmol) in MeOH (100 mL) was added sodium borohydride (2.2 g, 59.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before it was quenched with water (5.0 mL). Evaporation of solvents afforded light yellowish oil which was re-dissolved in EtOAc and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (9.6 g, 95%) as colorless oil. MS: 188.0 & 190.0 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:5][C:4]=1[F:20].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32].Cl>ClCCl>[Cl:2][C:3]1[C:4]([F:20])=[CH:5][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)C1CCNC(c2cc(F)c(Cl)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Methyl 2-(4-chloro-3,5-difluorophenyl)piperidine-4-carboxylate hydrochloride (1.82 g, 5.58 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.430 mL, 13.95 mmol) and methyl carbonochloridate (0.527 mL, 6.70 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M HCl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated to yield dimethyl 2-(4-chloro-3,5-difluorophenyl)piperidine-1,4-dicarboxylate (1.83 g, 94%). MS m/z 348 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=[C:10]([C:17]([OH:19])=O)[N:9]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=1)=[O:19])[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2sccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2sccc2c(-c2ccccc2Cl)n1
Yield: 60.8 %

Procedure:
Operations are carried out as for example 7, starting from 2.9 g of 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 2.1 g of N,N-diethyl 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxamide, melting at 119° C., are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[N:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)(Cl)Cl>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:12]2[N:11]=[C:10]([C:7]3[S:6][C:5]([C@@H:2]4[CH2:3][O:4][C:32](=[O:34])[NH:1]4)=[N:9][CH:8]=3)[CH:15]=[CH:14][CH:13]=2)[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@@H](N)CO)s3)n2)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccnc(Nc2cccc(-c3cnc([C@@H]4COC(=O)N4)s3)n2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of (S)-2-amino-2-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}ethanol (220 mg, 0.67 mmol) obtained in Example 13, triethylamine (0.93 ml, 0.67 mmol) in chloroform (5 ml), triphosgene (70 mg, 0.24 mmol) was added while cooled to −78° C., and the mixture was stirred at the same temperature for 3 hours. The reaction solution was warmed to room temperature and water was added and it was extracted with ethyl acetate. After washed with a saturated saline solution, the organic layer was dried over magnesium sulfate. After concentrated, the residue was washed with ethanol and the title compound (41 mg, 17%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:29]C)=[C:6]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:9]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:8][C:7]2([CH3:28])[CH3:27].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[CH:10]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:9]([C:23]([F:24])([F:25])[F:26])([OH:22])[CH2:8][C:7]([CH3:27])([CH3:28])[C:6]=2[C:5]([OH:29])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2c(Br)ccc(O)c21
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.6 %

Procedure:
21 mg (0.043 mmol) of 8-bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.4 ml of a 1 M BBr3 solution and stirred for 19 hours at room temperature. After the reaction mixture is mixed with ice, saturated sodium bicarbonate solution is added drop by drop, and it is diluted with ethyl acetate. The organic phases are washed neutral as usual, and the residue that remains after the solvent is spun in is chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 17.1 mg (83.8%) of the desired compound (together with the Desbrom compound) is isolated.
Reaction SMILES: [C:1]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([OH:14])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(OCC)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[C:1]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([N:28]=[N+:29]=[N-:30])=[O:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1occc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)c1occc1C(=O)N=[N+]=[N-]
Temperature: 0 °C

Procedure:
2-Pivaloyl-3-furoic acid (1.96 g, 0.01 mol) was dissolved in acetone (40 ml) and the solution was stirred at 0° C. under nitrogen. Triethylamine (1.7 ml, 0.012 mol) was added, followed by ethyl chloroformate (1.24 ml, 0.013 mol) and the mixture was stirred for 11/2 hours. A solution of sodium azide (1.11 g, 0.017 mol) in water (4 ml) was added and the suspension was stirred for another 2 hours at 0° C. The solid was removed by filtration and the filtrate was diluted with water (25 ml). It was concentrated in vacuo to remove the acetone. The oil-water residue was extracted with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to an amber oil (2.06 g) of 87% purity by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1[N+](=O)[O-]

Procedure:
1.88 g of 5-methoxy-2-nitrophenol was dissolved in 20 ml of N,N-dimethylformamide. Thereafter, 1.53 g of potassium carbonate and 1.03 ml of allyl bromide were successively added to the reaction solution. After the disappearance of materials had been confirmed, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.09 g of the subject compound.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.[Li+].[CH3:11][CH:12]([N-]C(C)C)C.ICC.O>O1CCCC1>[CH2:11]([C:4]1[N:3]2[CH:7]=[CH:8][CH:9]=[C:2]2[CH:1]=[N:6][CH:5]=1)[CH3:12]
Reactant: CC(C)[N-]C(C)C
Reactant: c1cc2cnccn2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCI
Product: CCc1cncc2cccn12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.0 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1 was dissolved in 10 ml of tetrahydrofuran and then cooled to -78° C. under nitrogen atmosphere. To this solution was added 1.2 equivalents of LDA solution; the resulting mixture was stirred for 30 minutes; and 1 ml of iodoethane was added to the mixture while maintaining the temperature of -78° C. The reaction mixture was stirred for 30 minutes, warmed to room temperature and then poured into water. The organic layer was isolated and then concentrated to dryness to obtain 0.3 g of title compound.
Reaction SMILES: [CH2:1]([Br:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].COC(C)CO.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>>[Br-:17].[CH2:1]([N+:26]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCBr
Agent: COC(C)CO
Product: CCCCCCCCCCCCCCCC[N+](CC)(CC)CC
Product: [Br-]
Temperature: 75 °C
Reaction time: 96 h

Procedure:
Into a 2 L round-bottom flask was placed hexadecyl bromide (250 g), 2-methoxypropanol (250 mL), and triethylamine (200 mL). The flask was heated without stirring at 75° C. for 96 h and the contents were concentrated on a Rotavap at 75° C. and 20 mbar. To the residue, methyl tert-butyl ether (800 mL) was added. The slurry was vigorously stirred by a mechanical stirrer for 12 h, filtered, washed with 3 portions (400 mL each) of methyl tert-butyl ether, and dried in vacuum to obtain the product as a white solid in nearly quantitative yield.
Reaction SMILES: C(OC(C1C[CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)CC1)=O)C.[CH2:42]([O:44][C:45]([CH:47]1CCNCC1)=[O:46])C>>[C:38]([N:30]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:9][CH2:10][CH2:47][C:45]([OH:46])=[O:44])=[CH:17][CH:16]=2)=[O:19])[C@@H:21]([CH3:41])[CH2:22]1)(=[O:40])[CH3:39].[CH3:42][O:44][C:45](=[O:46])[CH2:47][CH2:10][NH:9][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:22][C@@H:21]2[CH3:41])=[O:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Reactant: CCOC(=O)C1CCNCC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCCC(=O)O)cc2)c2ccccc21
Product: COC(=O)CCNc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenylamino)-propionic acid was prepared following the procedure for (2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-4-carboxylic acid ethyl ester, substituting 3-amino-propionic acid methyl ester for piperidine-4-carboxylic acid ethyl ester to yield the (2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenylamino)-propionic acid methyl ester. The ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and lithium hydroxide (1N) was added and heated 50° C. for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to afford the product after HPLC purification.
Reaction SMILES: [I:1]Cl.[N-:3]=[N+:4]=[N-:5].[Na+].[OH:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[CH:19]=[C:18]([CH:20]=[CH2:21])[C:16](=[O:17])[NH:15][C:13]1=[O:14]>C(#N)C.C(Cl)(Cl)Cl.CO>[OH:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[CH:19]=[C:18]([CH:20]([N:3]=[N+:4]=[N-:5])[CH2:21][I:1])[C:16](=[O:17])[NH:15][C:13]1=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Reactant: ClI
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [N-]=[N+]=NC(CI)c1cn(COCCO)c(=O)[nH]c1=O
Yield: 34.8 %

Procedure:
Iodine monochloride (92 mg, 0.56 mmol) was added slowly during a five minute period to a suspension of sodium azide (129 mg, 2.0 mmol) in dry acetonitrile (10 ml) at ice-bath temperature with stirring. This mixture was stirred for a further 5 min., a solution of 1 (105 mg, 0.49 mmol) in dry acetonitrile (15 ml) was added, the reaction mixture was stirred at 0° C. for 30 min. The resulting red-brown colored reaction mixture was poured onto ice cold water (25 ml), the mixture was extracted with ethyl acetate (3×50 ml) and the ethyl acetate extract was washed with 5% aqueous sodium thiosulfate (50 ml). Drying the colorless ethyl acetate fraction Na2SO4), removal of the solvent in vacuo and purification of the residue obtained by elution from a silica gel column using chloroform:methanol (93:7, v/v) as eluent afforded 2c (65 mg, 34%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH:15]([N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:22]2[CH:21]=[N:20][N:19]([CH:15]([CH:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[CH2:16][C:17]#[N:18])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCOCC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 71.4 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.589 g, 0.00395 mol), 3-(tetrahydro-2H-pyran-4-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (1.30 g, 0.00392 mol), tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.0002 mol), and potassium phosphate (2.5 g, 0.012 mol) in 1,4-dioxane (10 mL, 0.1 mol) and water (1 mL, 0.06 mol) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to provide the desired product (890 mg, 71.36%). LCMS (M+H) 318.3
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:20]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19]>>[ClH:27].[CH2:17]([N:20]([CH2:21][CH:22]=[CH2:23])[CH:24]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH2:25][CH3:26])[CH:18]=[CH2:19]
Reactant: C=CCN(CC=C)CCCCl
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Product: C=CCN(CC=C)C(CC)c1c(C)ccc2[nH]nc(-c3ccccc3)c12
Product: Cl
Yield: 56.2 %

Procedure:
By the procedure similar to that described in Example 13, 3-phenyl-5-methylindazole (4.17 g) and diallylaminopropyl chloride (4.17 g) were treated to obtain 4.3 g of 1-diallylaminopropyl-3-phenyl-5-methylindazole hydrochloride (m.p. 81°-82° C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and isonicotinoyl chloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-isonicotinamide (65.5 mg, 77.9%) as a white solid: mp 225-230° C.; FAB-HRMS m/e calcd :for C23H24N4O2S (M+H)+ 421.1698, found 421.1698.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23](=O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:40]5[CH:41]=[CH:42][C:43]6[N:31]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)[C:32]7[C:37]([C:38]=6[CH:39]=5)=[CH:36][CH:35]=[CH:34][CH:33]=7)([C:40]5[CH:41]=[CH:42][C:43]6[N:31]([C:25]7[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=7)[C:32]7[C:37]([C:38]=6[CH:39]=5)=[CH:36][CH:35]=[CH:34][CH:33]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Yield: 83.8 %

Procedure:
The chemical compound can be obtained by performing nucleophilic addition reactions twice between starting materials and different aniline aromatic rings (e.g. carbazole or triphenylamine) along with using non-metal catalytic Eaton's reagents on different chemical equivalent basis. First, 10-phenyl-11H-indeno[1,2-b]quinolin-11-one (860 mg, 2.80 mmol) and 9-phenyl-9H-carbazole (1500 mg, 6.10 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 800 μl of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 20 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 1820 mg of 10-phenyl-11,11-bis(9-phenyl-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 83.8%.
Reaction SMILES: C(C1OC2C=C(C[Br:13])C=CC=2N=1)#N.[C:14]([C:16]1[O:17][C:18]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)#[N:15]>>[Br:13][CH2:25][C:24]1[C:18]2[O:17][C:16]([C:14]#[N:15])=[N:20][C:19]=2[CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Reactant: Cc1cccc2nc(C#N)oc12
Product: N#Cc1nc2cccc(CBr)c2o1

Procedure:
When the 2-cyano-6-bromomethylbenzoxazole in Example 10, Step 2 is replaced with 2-cyano-7-methylbenzoxazole, 7-bromomethyl-2-cyanobenzoxazole is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:14])[CH:3]=1.C(N(CC)CC)C.Cl[C:23]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1.CO>[Cl:33][C:30]1[CH:31]=[N:32][C:23]([N:11]2[CH2:12][CH:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:14])[CH3:13])[CH2:10]2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Cc1cc(F)ccc1N(C)C1CNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1N1CC(N(C)c2ccc(F)cc2C)C1
Temperature: 75 °C
Yield: 82.6 %

Procedure:
To mixture of N-methyl-N-(2-methyl-4-fluoro-phenyl)azetidin-3-amine (D56) (110 mg, 0.566 mmol) and triethylamine (0.18 ml, 0.849 mmol) in tetrahydrofuran/methanol (3/1 ml) Methyl 2,5-dichloronicotinate (116.82 mg, 0.566 mmol) was added and the mixture was heated at 75° C. for 12 hours. Solvents were evaporated and the residue was purified by SNAP-Si cartridge (10 g) eluting with cyclohexane/ethyl acetate from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D87) (170 mg)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[OH:12].[Br:13][CH2:14][CH2:15]Br>O.C(O)C>[Br:13][CH2:14][CH2:15][O:12][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[Cl:11]
Reactant: BrCCBr
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Yield: 67.4 %

Procedure:
A solution of sodium hydroxide (7.8 g, 0.195 mol) in water (20 ml) was added to a solution of 2,4,6-trichlorophenol (38.0 g, 0.192 mol) in ethanol (200 ml). 1,2-dibromoethane (47 g, 0.25 mol) was then added and the resultant mixture was refluxed overnight. On cooling, the solid was filtered off and the filtrate concentrated under reduced pressure. Ether was added to the residue and the solution was then washed with dilute sodium hydroxide solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethanol to give 1-bromo-2-(2,4,6-trichlorophenoxy)ethane as a white solid (39.4 g). A mixture of the 1-bromo-2-(2,4,6-trichlorophenoxy) ethane (20.0 g, 0.066 mol), triethylamine (6.7 g, 0.066 mol) and propylamine (3.9 g, 0.066 mol) in ethanol (500 ml) was then refluxed overnight. After removal of the solvent by evaporation, the residue was dissolved in ether, washed with water and dried (MgSO4). Evaporation of the solvent left an oil which, after flash chromatography on silica gel using chloroform as the eluant, yielded N-propyl-N-2-(2,4,6-trichlorophenoxy)ethylamine as an oil (12.6 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11](=[O:27])[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=1)[CH2:13]OCC.B(Br)(Br)[Br:29]>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11](=[O:27])[C:12]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=1)=[CH2:13].[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11](=[O:27])[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=1)[CH2:13][Br:29]
Reactant: BrB(Br)Br
Reactant: CCOCC(C(=O)c1ccc(OC)cc1OC)c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: C=C(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1
Product: O=C(c1ccc(O)cc1O)C(CBr)c1ccc(O)c(O)c1

Procedure:
0.406 g (1.08 mmol) of 1-(2,4-dimethoxyphenyl)-2-(3′,4′-dimethoxyphenyl)-1-oxo-3-ethoxy-propane were reacted with boron tribromide (10.84 mmol) in 22 mL dichloromethane for three days by the method of Bannwart C. et al. Finn. Chem. Lett. 11 120 (1984). Workup and chromatography of the reaction product afforded 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene as the minor product and 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-3-bromo-propane as the major product.