Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(I)cc1
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: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Under an argon gas atmosphere, 70.0 g (407 mmol) of 2-naphthalene boronic acid, 115.1 g (407 mmol 1) of 4-bromoiodobenzene, 9.40 g (8.14 mmol) of tetrakis(triphenylphosphine)palladium(0), 1.2 L of toluene and 600 ml of 2M sodium carbonate solution were mixed, and stirred for 20 hours at 90 degrees C. After the reaction in the mixture was over, toluene was distilled away therefrom, and the mixture was added with methanol, such that precipitated solid was separated by filtration. By recrystallizing the obtained solid by acetic ether and methanol and subsequently drying the solid, 77.2 g of 2(4-bromophenyl)naphthalene was obtained with an yield of 67%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:13][C:3]1[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)c(Cl)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1F
Reaction time: 120 h

Procedure:
To a solution of methyl 5-amino-4-chloro-2-fluorobenzoate (248 mg, 1.22 mmol) and pyridine (0.12 mL, 1.46 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.10 mL, 1.34 mmol). After 5 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(CBr)ccc1Cl
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4-chloro-3-nitrophenyl)methanol (5.0 g, 26.6 mmol) in toluene (100 mL) was added phosphorus tribromide (0.879 mL, 9.32 mmol) at 40° C. The reaction mixture was stirred at 100° C. for 15 mins and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.CC(C[AlH]CC(C)C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:16][C:13](=[C:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[CH2:3][OH:2])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.11 g (4.45 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 40 mL of hexanes and 40 mL of CH2Cl2 was added a solution of 26.7 mL (26.7 mmol) of DIBAL-H (1M solution in THF followed by stirring for 1 h at −78° C. Then the reaction mixture was warmed to rt for 1.5 h and 8 g of sodium sulfate decahydrate was added to quench the reaction followed by stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as white solid. 1NMR (CDCl3) δ 3.99 (s, 2H), 4.03 (s, 2H), 4.35 (s, 2H), 4.54 (s, 1H), 6.70-6.80 (m, 3H), 7.30-6-7.40 (m, 8H). Mass Spectrum: m/e=446 (M+1 35Cl, 35Cl) and 448 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CCCCCC.C(OCC)C.O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:34][CH:33]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2ccnc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 11.8 g. of 1-[(benzyloxy)methyl]imidazole in 100 ml. of anhydrous tetrahydrofuran and 50 ml. of anhydrous diethyl ether a solution of 38 ml. of a 20% butyllithium suspension in hexane dissolved in 75 ml. of anhydrous diethyl ether was added drop-wise with stirring at room temperature. Thereafter a solution of 14.6 g. of 4-chlorobenzophenone in 100 ml. of anhydrous tetrahydrofuran and 50 ml. of anhydrous diethyl ether was added drop-wise at room temperature. The mixture was kept for three hours and then extracted with a dilute acid solution. The acidic aqueous layer was made alkaline with 2 N sodium hydroxide solution and extracted with diethyl ether. Part of the ether was removed by evaporation and the residue washed with water. The ether solution was again concentrated and the desired compound crystallised from a mixture of toluene and petroleum ether (boiling range 28°-40° C.). Melting point of the product was 114.5°-117° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([O:23]C(C)(C)C)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH3:8].[CH2:14]([S:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](SCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: O=C(O)[C@@H]1C[C@H](SCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 36 h
Yield: 16.9 %
Yield: 10 %

Procedure:
To a solution of (2S,4S)-4-Benzylsulfanyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 2, 130 mg, 3.3 mmol) in dichloromethane (2.5 ml) was added trifluoroacetic acid (2.5 ml) and the mixture stirred at room temperature under a nitrogen atmosphere for 36 hours. The solvent was removed under reduced pressure and the residue purified by ion-exchange chromatography using Dowex™ 50WX8-200 resin eluting first with water and then with 10% aq ammonia to give the title compound (66 mg, 75%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1>C(O)C.[Pd]>[CH3:15][C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[N:3][C:4]=1[CH3:16]
Reactant: CCOC(=O)C=Cc1cc(C)c(C)nc1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(C)c(C)c1
Yield: 80 %

Procedure:
Ethyl 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylate (32.7 gZ) in ethanol (500 ml) was hydrogenated at 25°-30° and 344 kPa using palladium-on-charcoal catalyst (5%, 3 g). The mixture was filtered and the filtrate was evaporated to an oil which was partitioned between chloroform and 2 N hydrochloric acid. The aqueous phase was made basic with aqueous sodium hyroxide, extracted with chloroform and the chloroform extracts were evaporated to give ethyl 3-(5,6-dimethyl-3-pyridyl)propionate (21.8 g, 80%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1.CCN(CC)CC>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:21]=[N:20][N:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3cnn(-c4ccccc4)c3)c(N(C)C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 43.3 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate (150 mg, 0.46 mmol) in dioxane (10 mL) was added phenylboronic acid (112 mg, 0.92 mmol), Cu(OAc)2 (123 mg, 0.68 mmol), pyridine (31 mg, 0.39 mmol) and Et3N (310 mg, 2.3 mmol). The resulting solution was stirred for 36 h at room temperature and concentrated under vacuum. The residue was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(1-phenyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (80 mg, 43%).
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:11]([O:18][N:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C(=NOCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of ethanol (100 mL), potassium carbonate (8.98 g, 65 mmol), and O-benzylhydroxylamine hydrochloride (10.0 g, 62.7 mmol) was added benzaldehyde (6.65 g, 62.7 mmol). The mixture was refluxed for 5 hours, allowed to cool to room temperature, and diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the title compound as a yellow oil (14.96 g, 119%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[ClH:1].[C:17]1([N:23]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][N:9]=[CH:10][C:11]=4[C:2]3=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Reactant: NNc1ccccc1
Solvent: CO
Product: Cl
Product: O=c1c2c[nH]c3ccncc3c-2nn1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.60 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.25 g of phenylhydrazine in 32 ml of methanol is stirred at 22° for 18 hours, then refluxed for 3 hours. The resultant slurry is allowed to cool down to room temperature and filtered, obtaining 2-phenyl-pyrazolo[4,3-c][1,6]-naphthyridin-3(5H)-one hydrochloride, mp 310°; IR (KBr) 750, 756, 777, 802, 843 cm-1. This hydrochloride salt is dissolved in 1N sodium hydroxide and filtered. Ammonium chloride (10 g) is added to the filtrate, the resulting precipitate is collected, and is crystallized from methanol to yield the free base, 2-phenyl-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one, m.p. 334°-337°.
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([OH:14])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6].O[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2](=[O:20])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([O:14][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: O=C(CO)OCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoic acid (150 mg, 0.496 mmol), benzyl 2-hydroxyacetate (165 mg, 0.992 mmol), DMAP (121 mg, 0.992 mmol), and EDC (285 mg, 1.489 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 3 h to achieve completion. The reaction mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum to give 2-(benzyloxy)-2-oxoethyl 3-(N-(2-amino-2-oxoethyl)-methylsulfonamido)-4-methoxybenzoate (180 mg, 81% yield).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH3:12]>>[CH3:11][S:8]([C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: N
Product: CS(=O)(=O)c1cccnc1N
Temperature: 25 °C

Procedure:
The mixture of 800 mg of 2-chloro-3-(methylsulfonyl)pyridine (synthesized according to a method disclosed in J. Org. Chem. 1979, 44, 3080-3082) and 60 mL of aqueous ammonia, was stirred overnight in a sealed-tube at 175° C. After cooling back to room temperature, the mixture was extracted with diethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered. The filtrate was concentrated under reduced pressure, and 473 mg of 3-(methylsulfonyl)pyridine-2-amine [162-1] was obtained as a light orange solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].C[Si]([CH2:8][CH2:9][O:10][C:11]#[CH:12])(C)C.[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:9]([O:10][C:11]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]=[N:1][CH:12]=1)[CH3:8]
Reactant: Cc1ccccc1
Reactant: C#COCC[Si](C)(C)C
Reactant: [N-]=[N+]=[N-]
Product: CCOc1cnnn1-c1ccccc1
Temperature: 25 °C

Procedure:
The azide substance prepared in 1) of Example 7 and (trimethylsilyl)ethoxyacetylene were dissolved in 3.0 ml of toluene and the solution was stirred for one night under heating to reflux. After the reaction solution was cooled down to room temperature, the residue was separate and purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to give 98 mg of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH2:40]([N:48]1[CH:52]=[C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (160 mg, 0.2277 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (82 mg, 0.2733 mmol) in sodium carbonate (61 mg, 0.5694 mmol), Pd(PPh3)2Cl2 (8 mg, 0.0113 mmol), toluene/ethanol/water (3/2/1 ml) to give 160 mg (100% yield) of the titled compound. MS: m/z=704.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[NH:9]2)[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]3=[N:35][N:34]=[N:33][N:9]23)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)Nc1nnnn1-2
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)n1nnnc1N2
Yield: 51.2 %

Procedure:
A mixture of intermediate 9 (0.0014 mol) in toluene (10 ml) was stirred and refluxed for 48 hours, then brought to room temperature and the solvent was evaporated till dryness. The residue was taken up in DCM. The solvent was evaporated till dryness. The residue was purified by column chromatography over kromasil® (10 μm) (eluent: DCM/MeOH/Et3N 95/5/0.5). The pure fractions were collected and the solvent was evaporated. The residue (0.4 g, 57%) was washed with diethyl ether. The precipitate was filtered off and dried under a vacuo, yielding 0.35 g (50%) of 9-(3-chlorophenyl)-α-(4-fluorophenyl)4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol (compound 2), mp. 180° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][OH:19])=[O:17])=[O:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(Cl)Cl>[C:4]1([NH:7][C:8](=[O:9])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][O:19][C:30](=[O:32])[CH3:31])=[O:17])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)ONC(=O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of SAHA (0.43 g, 16.3 mmol) in pyridine/CH2Cl2 (5/5 mL) was added acetic anhydride 1-hydroxybenzotriazole (153 μL, 16.3 mmol). After stirring for 18 h at RT, the solvent was removed, and the material was without further purification. 1H NMR (DMSO-d6) δ 11.71 (br s, 1H), 10.01 (br s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.44 (dd, J=7.6, 7.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.35-2.20 (m, 2H), 2.30 (s, 3H), 1.82-1.58 (m, 4H), 1.58-1.36 (m, 4H). MS (EI): cal'd (MH+) 307.1, exp (MH+) 307.2.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[OH-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1I.O>CN(C)C=O>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1[O:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(O)cc1C(C)C
Reactant: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Temperature: 5 °C

Procedure:
3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1Br
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COc1ccccc1Br)c1ccccc1
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
(1)-(i) A suspension of 6.72 g of 60% sodium hydride in 40 ml of tetrahydrofuran is added dropwise to a solution of 24.17 g of 2-bromophenol in 210 ml of tetrahydrofuran at 4° C. and the mixture is stirred at the same temperature for 15 minutes. A solution of 30.66 g of phenacyl bromide in 60 ml of tetrahydrofuran is added dropwise to the mixture. The mixture is stirred at the same temperature for 30 minutes and further refluxed for 2.5 hours. The reaction mixture is evaporated to remove solvent, and water is added to the residue. The aqueous mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography and recrystallized from a mixture of ethyl acetate and n-hexane to give 21.49 g of (2-bromophenyl)(benzoylmethyl)ether as colorless needles.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][CH2:17][N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[C:20](=[N:33]O)[C:19]1=[O:35])(C(C)(C)C)(C)C>ClCCl.CO.[Zn]>[NH2:33][C@H:20]1[C:21]2[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[N:25][C:24]=2[N:18]([CH2:17][CH2:16][OH:15])[C:19]1=[O:35]
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N[C@@H]1C(=O)N(CCO)c2ncccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.5 %

Procedure:
Add trifluoroacetic acid (124.0 mL, 1.64 mol) in several portions to a solution of 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7-hydroxyimino-pyrido[2,3-d][3]benzazepin-6-one (155.0 g, 389.9 mmol) in a mixture of dichloromethane (620 mL) and methanol (310 mL) in an ambient temperature water bath. Add zinc (76.5 g, 1.2 mol) in several portions so that internal temperature was maintained at 33-38° C. Stir for 15 hours at ambient temperature. Filter mixture through Celite®, wash with 10% methanol/dichloromethane (100 mL) and concentrate the filtrate. Add dichloromethane (0.5 L) and ice (500 g), stir and basify with a 50% aqueous solution of NaOH. Filter out solids, separate filtrate layers. Extract from aqueous with dichloromethane (2×100 mL), and concentrate combined organics. Slurry solids in hexane, and then filter and dry under high vacuum to obtain the racemate of the title compound as a light yellow solid (74.0 g, 274.8 mmol, 71%). Purify the material on a Chiralpak® AD column eluting with ethanol (0.2% dimethethylamine): acetonitrile (0:100 to 100:0) to obtain the title compound (35.0 g, 130 mmol, 33.3%) as a white solid. MS (m/z): 270 (M+1); [α]Na25=+187.83° (c=6.9, methanol).