Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.C(O)(=O)C.[Fe]>[CH3:1][N:2]([C:9](=[O:19])[C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C(=O)c1ccc(N)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A mixture of N-methyl-N-(4-nitrobenzoyl)aniline (1.18 g) and iron powder (2.57 g) in a mixture of ethanol (30 ml) and acetic acid (6 ml) was stirred at 80° C. for 3 hours and the mixture was cooled to ambient temperature. The mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform and neutralized with saturated aqueous sodium hydrogen carbonate. The solution was filtered through Celite again and the organic phase of the filtrate was washed with brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give N-methyl-N-(4-aminobenzoyl)aniline (754 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:47])[C:21]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>CO>[C:20]1([CH3:47])[C:21]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH2:1]([N:8]([CH3:19])[C:9](=[O:18])[C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C(N)c1ccccc1
Agent: Cc1ccccc1C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c1ccccc1C
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1

Procedure:
In a preferred embodiment, (RS)-N-benzyl-N-methyl-2-phenylglycinamide (10.0 g) was treated with di(o-toluoyl)-L-tartaric acid (15.2 g) in methanol (167 mL) at 20° C. The precipitated the salt was filtered and washed with methanol, then dried providing (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate (11.73 g, 46.6%) with 92.7% d.e. (chiral HPLC). This material (1.00 g) was reslurried in hot methanol (8.8 ml) to provide (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 99% d.e. (0.79 g, 79% recovery) after filtration, washing and drying. The tartrate salts formed as described maybe broken to provide the free amine of formula C, i.e. (S)-N-benzyl-N-methyl-2-phenylglycinamide, which may be advantageously purified by the formation of a salt with an achiral acid in the presence of appropriate solvents, e.g. precipitation of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride from mixtures of propan-2-ol and tert-butyl methyl ether as described.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]([CH3:17])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)([OH:3])=O.[OH2:22]>C(Cl)Cl.C(OCC)(=O)C>[O:3]=[C:1]1[C:13]2[CH:12]=[CH:11][C:10]([CH:14]([CH3:17])[C:15]([NH2:16])=[O:22])=[CH:9][C:8]=2[CH2:7][CH2:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: O
Reactant: CC(C#N)c1cccc(CCc2ccccc2C(=O)O)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C

Procedure:
2-[3-(2-Carboxyphenethyl)phenyl]propionitrile (26 g.) is added to polyphosphoric acid (135 g.) [prepared from orthophosphoric acid (d = 1.7; 430 g.) and phosphorus pentoxide (500 g.)] and the emulsion obtained is heated for 1 hour at 100°C. After cooling, the reaction mixture is taken up in water (200 cc.) and methylene chloride (200 cc.). The organic layer is decanted, washed with a saturated solution of sodium bicarbonate (2 × 100 cc.) and then with water (2 × 100 cc.) and is finally dried over anhydrous sodium sulphate (50 g.). After evaporation of the solvent under reduced pressure (20 mm.Hg) at 60°C., the oil obtained is taken up in ethyl acetate (80 cc.). The product which crystallises is filtered off to give 2-(5-oxo-10, 11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (6 g.), melting at 175°C. After recrystallisation from ethanol, the product melts at 181°C.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH3:5])[CH3:3].Cl[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:7][NH:1][CH:2]([CH2:4][CH3:5])[CH3:3].[C:7]([NH:1][CH:2]([CH2:4][CH3:5])[CH3:3])([O:9][CH3:10])=[O:8]
Reactant: COC(=O)Cl
Reactant: CCC(C)N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)NC
Product: CCC(C)NC(=O)OC

Procedure:
N-Methyl-2-aminobutane was prepared from 2-aminobutane (24.7 g, 333 mmol) by reaction with methyl chloroformate (29 mL, 375 mmol) in dichloromethane (700 mL) containing 4-dimethylaminopyridine (4.25 g, 35 mmol) and triethylamine (58.5 mL, 415 mmol). N-carbomethoxy-2-aminobutane was isolated in 100% yield following washing of the reaction solution with water and 0.1N hydrochloric acid, drying of the solvent over sodium sulfate and rotary evaporation of the solvent. An ethereal solution of the product was added dropwise to a stirred suspension of lithium aluminum hydride (19.0 g, 500 mmol) in ether (1 L). After destruction of the aluminum and lithium complexes by careful addition of water (10 mL), 10% sodium hydroxide (10 mL) and water (57 mL), the solids were filtered and the ether was distilled off at atmospheric pressure. The residue was distilled to give 14 g of N-methyl-2-aminobutane as a clear colorless liquid (b.p.=74°-76° C./720 mm).
Reaction SMILES: [CH3:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4].C1(C)C=CC=CC=1.C(O)(=O)C.[CH3:18][SiH:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:28][SiH:19]([CH3:18])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH2:25][CH2:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4])=[CH:22][CH:21]=1
Reactant: C=Cc1ccc([SiH](C)C)cc1
Reactant: CO[SiH](C)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CO[SiH](CCCc1ccc([SiH](C)C)cc1)OC
Temperature: 50 °C
Yield: 4.9 %

Procedure:
325 mg Of 4-imethylsilylstyrene, 212 mg of methyldimethoxysilane, and 83 mg of toluene were placed in a glass reaction vessel and 0.005 ml of acetic acid was added. Next, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 0.5 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of 4-dimethylsilylstyrene was 63.6% and (4-(dimethylsilyl) phenethyl)methyldimethoxysilane was produced at a yield of 4.9%. The yield of α-(4-(dimethylsilyl)phenyl)ethyl) methyldimethoxysilane was 1.8%.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[C:29]([CH2:31][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 392.97 g/mol.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1.[CH3:38][NH2:39].C(O)C>O1CCCC1>[CH3:38][NH:39][CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1cccc(OCC=CCBr)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC=CCOc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1-bromo-4-[3-(perfluoro-n-octyl)phenoxy]but-2-ene (12.9 g) in tetrahydrofuran (20 mL) is added to a solution of 40 wt % methyl amine (20 mL), ethanol (20 mL) and tetrahydrofuran (20 mL) at 40° C. The mixture is stirred at ambient temperature for 2 hr. and extracted in the normal fashion. The resulting oil is Kugelrohr distilled to give N-methyl-4-[3-(perfluoro-n-octyl)phenoxy]but-2-enamine.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=[C:4]([NH2:13])[N:3]=1.[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1>[NH2:13][C:4]1[N:3]=[C:2]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=1
Reactant: COCCc1c(C)nc(N)nc1Cl
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCOC
Reaction time: 7 h
Yield: 57.5 %

Procedure:
A mixture of 4-chloro-5-(2-methoxyethyl)-6-methylpyrimidine-2-ylamine (150 mg, 0.74 mmol), amylamine (0.86 ml) and dioxane (1.5 ml) was kept at 90° C. for 7 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (4% MeOH:CHCl3) to give the object compound (108 mg, 57.5%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B.O1CCCC1>O1CCCC1.C(OCC)C.O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1c(F)c(F)c(F)c(-c2ccccc2)c1F
Agent: B
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F

Procedure:
Under a dry argon atmosphere 2,4,5,6-tetrafluoro-[1,1'-biphenyl]-3-carboxylic acid (21.6 g, 0.08 mole) was dissolved in 150 ml of tetrahydrofuran with stirring. During a 45 minute period 6.9 g of a borane-tetrahydrofuran complex (0.001 molar solution in tetrahydrofuran) was added to the reaction mixture. After complete addition, the reaction mixture was stirred at room temperature for approximately 23 hours. Water (5 ml) was added slowly to the reaction mixture, and the resultant mixture was stirred for two hours. The mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in diethyl ether and water. The organic phase was separated, washed with three 200 ml portions of 2 N aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Filtration of the mixture and evaporation of the solvent from the filtrate gave 2,4,5,6-tetrafluoro-[1,1'-biphenyl]-3-methanol as an oil.
Reaction SMILES: C[Li].[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:7].[CH3:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH-:10]1[CH:11]=[CH:12][CH:8]=[CH:9]1.[CH-:10]1[CH:11]=[CH:12][CH:8]=[CH:9]1.[Zr+2:7]
Reactant: CCCCC
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [Li]C
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.00 ml (3.22 mmol) of a 1.60M ethereal solution of methyllithium are added dropwise at 0° C. to a solution of 500 mg (1.61 mmol) of the bisisopropyl-substituted compounds (Examples 23a and 23b) in 20 ml of pentane. The mixture is allowed to warm to room temperature, giving, after 12 hours, a cloudy, orange suspension, which is cooled to -78° C. and treated with 373 mg (1.61 mmol) of zirconium tetrachloride. After the mixture has been stirred at room temperature for 24 hours, the insoluble constituents are filtered off, and the solvent is removed in vacuo, giving the two diastereomers of the ansa-zirconocene as an orange powder in a crude yield of 300 mg (40%). The 1H-NMR spectrum shows the resonance signals of the two diastereomers in the ratio 1:1 (determined from the i-Pr groups).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][CH2:7][CH2:8][OH:9].[Cl:10][C:11]1[C:16](O)=[C:15]([Cl:18])[CH:14]=[C:13]([CH3:19])[CH:12]=1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH3:19])[CH:14]=[C:15]([Cl:18])[C:16]=1[O:9][CH2:8][CH2:7][O:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: OCCOc1nccs1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c(OCCOc2nccs2)c(Cl)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 2-(thiazol-2-yloxy)ethanol (6.39 g, 44.0 mmol), 2,6-dichloro-p-cresol (15.6 g, 88.0 mmol), azodicarboxylic-dipiperidide (22.2 g, 88.0 mmol) and PBu3 (85%, 38.3 mL, 132 mmol) in toluene (325 mL) was heated to reflux for 30 min. The mixture was allowed to cool to rt, filtered, and the precipitate was washed thoroughly with toluene. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (4×). The org. phase was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:19→1:9→1:4) yielded the title compound as a colourless solid (9.24 g, 69%). LC-MS: tR=1.06 min, ES+: 304.05.
Reaction SMILES: BrN1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[CH2:9](N(S(F)(F)F)[CH2:12][CH3:13])[CH3:10].C(=O)(O)[O-:19].[Na+]>ClCCl>[C:12]([O:7][CH2:6][CH3:5])(=[O:19])[CH3:13].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:9][CH3:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 1 h
Yield: 45 %

Procedure:
N-Bromosuccinimide (1,2 g) and diethylaminosulphur trifluoride (1,2 g) are added to a solution of the pivaloyl ester (49) (2 g) in dichloromethane (100 ml) at 0° C. After 1 hour, saturated sodium bicarbonate is added. The dichloromethane layer is dried (MgSO4), filtered and evaporated. The β-fluoropyranoside (50) is purified by silica gel column chromatography eluting with ethyl acetate:hexane (2:8), (yield 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH:23][CH3:24])[CH:17]=1)[CH3:13].[CH2:26](Cl)CCl>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]2[N:22]=[C:24]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=4[N:6]=3)[N:23]([CH3:26])[C:18]=2[CH:17]=1)=[O:25])[CH3:13]
Reactant: ClCCCl
Reactant: CCOC(=O)c1ccc(N)c(NC)c1
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc(Nc3nc4ccc(Cl)cc4s3)n(C)c2c1
Yield: 50.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester (1.2 g) was prepared by following General Procedure D starting from 6-chloro-benzothiazol-2-ylamine (1.2 g), 4-amino-3-methylamino-benzoic acid ethyl ester (1.2 g), thioCDI (1 g) and EDC (1.1 g) in DMF (20 mL).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound. ESI-MS (m/z): 358 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([C:14]#[CH:15])=[CH:17][CH:18]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: CC(=O)O
Solvent: CCO
Product: C#Cc1ccc(N=Cc2cccc(C(C)(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
3-tert-butyl salicylaldehyde (1) (0.70 g/3.93 mmol) and 4-ethynyl aniline (0.49 g/4.2 mmol) were dissolved in 100 ml of ethanol. Molecular sieves (3 Å, 15 g) and a few drops of glacial acetic acid were added and the mixture was stirred at room temperature for three days. After filtration over sodium sulphate and removal of the solvent, the residue was extracted several times with n-pentane. The solution was filtered again over sodium sulphate, and the solvent was removed. The title compound was obtained as a yellow powder. Yield: 43%.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[NH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1.CCCCCC>C(OCC)(=O)C>[Br:29][C:25]1[CH:24]=[C:23]([NH:22][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([NH:9][C:5](=[O:6])[CH2:4][C:2](=[CH2:3])[C:1]([OH:7])=[O:8])[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=C1CC(=O)OC1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
Itaconic anhydride (0.14 g, 1.25 mmol) was added portionwise to a solution of 0.1 g (0.30 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2 mL of ethyl acetate under N2. After stirring at room temperature overnight, the reaction solution was added into ice water and hexane. The product was collected, washed with water, ether and hexane, and dried in vacuo to give 0.09 g (68%) of yellowish brown solid; ESMS m/z 451.2 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[S:9][CH:10]=1)(=[O:3])[CH3:2].[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[S:9][C:10]=1[Br:21])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Temperature: 5 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (10 mL) of the crude compound (21 mmol) obtained in Example 64c in acetic acid was slowly added dropwise a solution (10 mL) of bromine (2.5 g, 31 mmol) in acetic acid, and the mixture was stirred at 0-10° C. overnight. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (4.0 g, 51%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](Br)=[N:6][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.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>[Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]([C:28]3[CH:29]=[CH:30][C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:39][CH:40]=3)=[N:6][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(Br)nn2C(C)C
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1c(Br)nn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of ethyl 3,6-dibromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.2 g, 3.08 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.935 g, 3.08 mmol) and Pd(PPh3)4 (0.178 g, 0.154 mmol) in 1,4-dioxane (33 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (1.17 g, 11.10 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.8 g, 67.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[CH:27](N1C2C=CC=CC=2N=N1)=[O:28]>O1CCCC1.ClCCl>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:16]([C:15]2[C:10]([S:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:7]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH:24]=[C:23]([CH3:25])[CH:22]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Reactant: O=Cn1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC=O)c2)c1

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (the free base of Compound No. 3-1, 50 mg, 0.14 mmol) was dissolved in anhydrous tetrahydrofuran (0.20 mL), a solution of N-formylbenzotriazole (19 mg, 0.13 mmol) in anhydrous tetrahydrofuran (0.2 mL) was added thereto, and then the mixture was refluxed for 16 hours. The mixture was diluted with dichloromethane (15 mL), and then the whole was washed with 2 N aqueous sodium hydroxide solution (4.0 mL) twice and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 60 mg of the target compound quantitatively as a colorless solid.