Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38](Cl)[N:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[N:37]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(C#N)cc(Cl)n2)c1F
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (4.73 g, 29.5 mmol) and 18-crown-6 (1.558 g, 5.90 mmol) were combined and treated with 20% potassium t-butoxide in THF (16.54 g, 29.5 mmol) in THF at 25° C. and stirred 15 min. 2,6-dichloro-4-pyridinecarbonitrile (5.1 g, 29.5 mmol) was added to the reaction mixture and stirred at ambient temperature for 4 days. A fine white precipitate was filtered off from the reaction mixture and washed with a small amount of DMSO. This material was partitioned between EtOAc and saturated aqueous NaHCO3, the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness to give 2-chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile (3.88 g, 13.06 mmol, 44.3% yield) as a white solid. The DMSO filtrate was treated with water and saturated aqueous NaHCO3 to give a purple precipitate that was filtered off, washed with water and air dried. This material was dissolved in DCM, dried over MgSO4, filtered and concentrated to dryness to give a purple solid. The residue was trituarated with EtOH, cooled in an ice bath, filtered and air dried to give a second batch of the desired product (3.65 g, 12.28 mmol, 41.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=0.82 Hz, 1H), 7.93 (d, J=0.73 Hz, 1H), 7.28-7.43 (m, 2H), 2.28 (d, J=1.74 Hz, 3H). LC-MS (ES+) m/z 296.95, 298.88 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([NH2:8])[NH:5][N:4]=1)[CH3:2].[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])=[CH:17][C:12]=2[N:11]=[N:10]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[NH:8][C:6]4[N:5]([N:4]=[C:3]([CH2:1][CH3:2])[N:7]=4)[C:20](=[O:21])[CH:19]=3)=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: CCc1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of 3-ethyl-1H-1,2,4-triazol-5-amine (150 mg, 0.89 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (500 mg, 2.15 mmol) and TsOH (8 mg, 0.04 mmol), and the reaction mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (20 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-ethyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (66.4 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])O[CH:10]=1)=[O:4].[NH2:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])[N:12]([CH2:13][CH2:14][NH2:15])[CH:10]=1)=[O:4]
Reactant: NCCN
Reactant: COC(=O)c1ccc(=O)oc1
Solvent: CCO
Product: COC(=O)c1ccc(=O)n(CCN)c1
Reaction time: 4 h

Procedure:
To a 500 ml 3-necked flask fitted with a magnetic stirrer bar, addition funnel, nitrogen inlet, and containing 2-oxo-2H-pyran-5-carboxylic acid methyl ester (coumalic acid methyl ester) (10.0 g, 65.0 mmol) and absolute ethanol 160 ml) was added, over 3-5 minutes at room temperature, a solution consisting of 1,2-diaminoethane (17.4 ml, 260 mmol) and abs. ethanol (50 ml). Stirring was continued for 4 hours at which time the suspension was filtered. Concentration of the flitrate gave 1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester which was used without purification.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:11]=[C:12]([NH2:28])[C:13]3[N:14]=[CH:15][N:16]([C:26]=3[N:27]=2)[C@@H:17]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[CH:9]=1)=[O:4].[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:11]=[C:12]([NH2:28])[C:13]3[N:14]=[CH:15][N:16]([C:26]=3[N:27]=2)[C@@H:17]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[CH:9]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: CO
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of 1 g of 2-(4-methoxycarbonylpyrazol-1-yl)adenosine in 10 ml of 40% methylamine in methanol is stirred in a closed flask at 20° C. until formation of a solution (3 to 5 hours). The produced solution is left to stand at the given temperature for additional 15 hours. The solution is then filtered with active charcoal and the filtrate is concentrated in vacuo. The evaporation residue, which is the amorphous form of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, is dissolved in 2 ml of dimethylsulfoxide and left to cool down freely to room temperature. The resulting turbid solution is added to 20 ml of methanol. The separated gel-like precipitate is stirred under the boil for 1.5-2.5 hours, wherein a powder-like suspension is formed. After cooling down, sucking off, and drying, 0.8 g of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine polymorph E is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)=[O:17].O.N.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][S:10]4(=[O:15])=[O:14])=[CH:7][C:2]=3[C:34]#[N:35])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3Br)CC2)c(C)c1
Reactant: CN(C)C=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Under a nitrogen stream, [2-bromo-4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (120 mg) described in Example 461 was dissolved in N,N-dimethylformamide (5 mL), zinc cyanide (28 mg) and tetrakistriphenylphosphine palladium(0)(55 mg) were added, and the mixture was stirred at 130° C. for 4 hr. After completion of the reaction, to the reaction mixture was added water/saturated aqueous ammonium chloride solution/28% aqueous ammonia (4:4:1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (68 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>CO.CC(O)=O>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (1.0 eq) and 4-chlorobenzaldehyde (1.0 eq) in MeOH:HOAc (10:1 v/v, 0.017M) was stirred for 15 min at rt prior to the addition of (polystyrylmethyl)trimethylammonium cyanoborohydride (3.5-5.0 mmol/g, 2.5 eq). The reaction mixture was shaken at rt overnight in a capped vial and then filtered through a plug of cotton wool. The resin was washed with MeOH and the combined filtrate and MeOH washings were concentrated under reduced pressure and purified by silica gel chromatography eluting with 5% MeOH in DCM to yield 1-{3-[(4-chlorobenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide. 1H-NMR (CD3OD, 400 MHz): δ 4.38 (s, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 6.76 (dd, J=2.0 Hz, 7.0 Hz, 2H), 7.20-7.45 (m, 7H), 7.81 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.89 (d, J=6.0 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.42 (s, 1H), 8.45 (d, J=4 Hz, 1H), 8.60 (s, 1H). MS (ES+): m/z 469 [MH+]
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:14]=[CH:15][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 7 h
Yield: 57.6 %

Procedure:
Anisole (0.25 mL) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridin-2(1H)-one (49 mg) in trifluoroacetic acid (0.5 mL), and the mixture was stirred at 65° C. for seven hours. Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred for further five hours, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1). The resulting crystals (25 mg) were recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (20 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:38])[CH:12]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:13][C:14]([C:16]2[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:18]=[CH:19][CH:20]=2)=[O:15])=[CH:7][CH:6]=1>CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:38])[CH:12]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH2:13][C:14]([C:16]2[NH:17][CH:18]=[CH:19][CH:20]=2)=[O:15])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)C(CC(=O)c2cccn2S(=O)(=O)c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)C(CC(=O)c2ccc[nH]2)c2ccc(OC)cc2)cc1
Yield: 87.8 %

Procedure:
30 ml of 1N aqueous solution of sodium hydroxide was added to a suspension of Compound 1 (3.0 g) according to Example 1 in acetone (60 ml), and the mixture was heated under reflux for 16 hours with stirring. After cooling, the acetone was removed by evaporation under reduced pressure and the resulting residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give 1.90 g (87.6%) of 1,2-di-(4-methoxyphenyl)-4-(2-pyrrolyl)-1,4-butanedione (Compound 10).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19].O.[OH-].[Li+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[C:4]([OH:6])=[C:18]([C:17]([O:21][CH3:22])=[O:20])[S:19][C:8]=2[CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CS
Reactant: COC(=O)c1ccc(Cl)c(C(=O)OC)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2sc(C(=O)OC)c(O)c2c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
Dimethyl 2,4-dichloroisophthaloate (11.95 g) and methyl thioglycolate (7.23 g) was dissolved in N,N-dimethylformamide, and lithium hydroxide monohydrate (3.81 g) added. The mixture was stirred at ambient temperature for 2 days, diluted with water and brought to pH 1 with hydrochloric acid. The solid was filtered, washed with boiling cyclohexane and dried by azeotropic removal of toluene to give dimethyl 4-chloro-3-hydroxybenzo[b]thiophene-2,5-dicarboxylate (13.44 g) as a beige solid, m.p. 127°-131° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:12][CH2:13][OH:14]>C(O)C>[OH:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCSc1ccc(O)cc1

Procedure:
4-Mercaptophenol (126 grams) was dissolved in 60 millimeters of ethanol. A solution of KOH (58 grams) dissolved in ethanol (150 millimeters) was added under a nitrogen blanket. 2-Chloroethanol (83 grams) was then added slowly and the combination allowed to react for 11/2 hours. The product was filtered and the volatiles stripped off. The weight of product was 172 grams.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>O>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: Nc1cccnc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCl)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminopyridine (350 mg) and sodium hydroxide (0.6 g) were dissolved in water (8 mL) and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (1.19 mL) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was extracted with dichloromethane and organic layer was concentrated and purified by column chromatography, eluting with 0-60% ethyl acetate/cyclohexane to give the title compound (0.10 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=O>>[F:39][C:35]1[CH:34]=[C:33]([C:31]2[N:27]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:28][CH:30]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)c1cccc(F)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)cs2)C1

Procedure:
100 mg (about 0.211 mmol) of the compound from Example 115A and 55 mg (0.253 mmol) of 2-bromo-1-(3-fluorophenyl)ethanone were reacted according to the General Method 3. Yield: 78 mg (69% of theory).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[O:26][CH2:25][O:24][CH2:23][C:22]=3[CH:21]=[C:20]([F:28])[CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:28][C:20]1[CH:19]=[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:27]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2cc(F)cc3c2OCOC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cc(F)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
The mixture of 2-[(6-fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (61) (560 mg, 1.45 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (62) as white solid (520 mg, 100%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:32][CH2:31][N:30]([CH:29]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:35][CH2:34]2)=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
141 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (86 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:10])[C:7]=1[O:8]C.B(Br)(Br)[Br:12].CO>C(Cl)Cl>[NH2:10][C:6]1[C:5]([Br:12])=[CH:4][CH:3]=[CH:2][C:7]=1[OH:8]
Reactant: COc1c(N)cccc1Br
Reactant: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Nc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To an ice cooled solution of 6-bromo-2-anisidine (1.01 g, 5 mmol) in methylene chloride (30 mL) was slowly added a 1.0 M solution of boron tribromide in methylene chloride (10 mL, 10 mmol) via syringe. The reaction was slowly warmed to room temperature and stirred overnight. Methanol (10 mL) was added and the solvents removed by rotoevaporation to give the title compound (0.87 g, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12]([N:11]([CH3:15])[CH3:10])=[O:13])=[N:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: NNc1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)NNc1ccc(F)cn1
Yield: 77 %

Procedure:
A solution of (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol), dimethylcarbamyl chloride (505 mg, 4.72 mmol) and DIPEA (1.01 g, 7.86 mmol) in DCM (20 mL) was stirred at reflux for 16 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo and then trituration with diethyl ether gave the title compound (600 mg, 77%). 1H NMR (400 MHz, CDCl3): 2.99 (6H, s), 6.46 (2H, m), 6.75 (1H, dd, J 9.1, 3.5), 7.22-7.32 (1H, m), 8.03 (1H, d, J 2.7).
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](B(O)O)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O.O.C1C=CC=CC=1>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC1Cc2ccc(-c3ccc(C(N)=O)cn3)cc2C1
Yield: 92.2 %

Procedure:
5.00 g (20.3 mM) of 2-hexylindan-5-boronic acid, 2.79 g (17.8 mM) of 6-chloronicotinamide, 20 ml of ethanol, 30 ml of benzene, 27.9 ml of 2M-sodium carbonate aqueous solution and 1.19 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 2 hours under stirring. After the reaction, the reaction mixture was poured into water to obtain an insoluble matter. The insoluble matter was recovered by filtration. Separately, the filtrate was subjected to vacuum distillation to remove the organic solvent and poured into water to obtain an insoluble matter. The insoluble matter was added to the above-prepared insoluble matter. To the resultant mixture, 100 ml of acetone was added, followed by cooling with ice to precipitate a crystal. The crystal was recovered by filtration and washed with acetone, followed by drying to obtain 5.30 g of 2-hexyl-5-(5-carbamoylpyridine-2-yl)indan (Yield: 92.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([Cl:23])[CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][C:18]=1[Cl:23])=[O:4]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: COC(=O)c1ccn2cncc2c1Cl
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1Cl
Temperature: 110 °C
Yield: 49.8 %

Procedure:
A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (300 mg, 1.43 mmol), 4-bromo-2-chloroaniline (354 mg, 1.72 mmol), Pd2dba3 (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (131 mg, 0.28 mmol) and K3PO4 (424 mg, 2.00 mmol) in toluene (5 ml) was degassed and then heated at 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. The resultant mixture was washed with water and brine, then loaded onto a 10 g Isolute® SCX-2 cartridge which was eluted with methanol and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl actetate in DCM) to afford the title compound as a yellow oil (271 mg, 50%). LCMS (method B): RT=3.65 min, [M+H]+=381/383.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:20]=1>>[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24](/[CH:28]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[N:20]=1
Reactant: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Reactant: O=C1Cc2ccccc2N1
Product: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12

Procedure:
Synthesized according to the method of Example A19, utilizing indolin-2-one (14.5 mg, 0.11 mmol) and (E)-3-(2-(1-methyl-1H-imidazol-2-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazole-6-carbaldehyde (41.6 mg, 0.11 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a yellow material (35.4 mg, 65%); MS ESI 498.4 [M+H]+, calcd for [C28H31N5O2Si+H]+ 498.7.