Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16]C)=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([OH:16])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)[N:3]=1
Reactant: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
To a solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5,6-dimethoxy-phenyl)-methanone (30 mg, 0.0636 mmol, Example 261) in methylene chloride (20 mL) cooled to 5° C. was added aluminum chloride (129 mg, 0.954 mmol, Fluka). The reaction mixture was stirred at room temperature for 24 hours and quenched with water. Tetrahydrofuran (40 mL) was added and the layers were separated. The organic layer was washed with water (1×5 mL), brine (1×5 mL) and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with ethyl acetate) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-hydroxy-5-methoxy-phenyl)-methanone as yellow solids (15 mg, 52%). HR-MS (ES, m/z) calculated for C18H22N5O5SF2 [(M+H)+] 458.1307, observed 458.1304.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[N:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2nc(Cn3ncc(N)n3)cs2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[I-:23]>S([O-])([O-])(=O)=O.[Ag+].[Ag+].CO>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])[CH:6]=[C:7]([Br:21])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([I:23])[CH:14]=1
Reactant: [I-]
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)cc2)c(Br)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(I)c2)c(Br)c1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Methyl[3,5-dibromo-4-(4-methoxyphenoxy)phenyl]acetate (1.0 g, 2.3 mmol), silver (I) sulfate (1.6 g, 4.6 mmol) and methanol (10 mL) was stirred in the dark at −78° C. Iodide (1.2 g, 4.6 mmol) was added and the reaction mixture was allowed to reach room temperature after 10 minutes. The yellow precipitate was filtered off, the eluate dissolved in ethyl actetate and washed with water. After concentration of the organic phase, 0.82 g (64%) of methyl [3,5-dibromo-4-(4-methoxy-3-iodophenoxy)phenyl]acetate was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:17][CH2:16]2)[CH:11]=1)=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C2CC2)no1
Agent: Cl
Solvent: CO
Product: NCc1cc(C2CC2)no1
Yield: 53 %

Procedure:
Crude 5-(tert-butoxycarbonylaminomethyl)-3-cyclopropylisoxazole (Method 3) (37.4 g, 0.157 mol) and 3M hydrochloric acid (80 ml) in methanol (100 ml) was heated at 50° C. for 2 hours. The methanol was removed by evaporation and aqueous residue washed with DCM. The aqueous layer was adjusted to pH 12 by careful addition of 40% aqueous sodium hydroxide solution and then extracted with DCM (×4). The extracts were combined, washed with brine, then dried (Na2SO4) and the volatiles removed by evaporation to give the title compound (11.5 g, 53%) as oil.
Reaction SMILES: [BH4-].[Li+].O1CCCC1.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C@@H:22]([C:23]4[CH:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[C:25]([Cl:33])[CH:24]=4)[C@H:21]([C:34]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@@H:40]([CH2:43][OH:44])[O:39][CH2:38]4)=[O:35])[NH:20][C:19]43[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][CH2:45]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C@@H:22]([C:23]4[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=[C:25]([Cl:33])[CH:24]=4)[C@H:21]([C:34]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@@H:40]([CH2:43][OH:44])[O:39][CH2:38]4)=[O:35])[NH:20][C:19]43[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][CH2:45]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc([C@H]2[C@H](C(=O)N[C@@H]3CC[C@@H](CO)OC3)NC3(CCC(C)(C)CC3)[C@@]23C(=O)Nc2cc(Cl)ccc23)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@@H]1CC[C@@H](CO)OC1)[C@H](c1cc(Cl)cc(CO)c1)[C@]21C(=O)Nc2cc(Cl)ccc21
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Lithium borohydride (26 mg, 1.25 mmol) was gradually added to a tetrahydrofuran (4 ml) solution of the compound (107 mg, 0.17 mmol) obtained in Step 2 of Example 22 at room temperature and the resulting mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography [methanol:ethyl acetate=1:9 (v/v)] to give 69 mg (68%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[Br:9]Br>CCOCC>[Br:9][CH2:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CCl
Solvent: CCOCC
Product: CC(C)(CCl)C(=O)CBr
Yield: 79.2 %

Procedure:
134.5 g (1 mol) of 1-chloro-2,2-dimethyl-butan-3-one were dissolved in 500 ml of ether. 51 ml (1 mol) of bromine were added dropwise at room temperature, while cooling slightly, at a rate such that it was continuously consumed. Thereafter, the solution was stirred into 1,000 ml of ice-water and the organic phase was separated off, rinsed with 250 ml of water, dried over sodium sulphate and distilled. 169 g (80% of theory) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one of boiling point 95°-106° C./13 mm Hg were obtained. ##STR12##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:9]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cncc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 5-bromonicotinic acid and 3-trifluoromethylaniline were converted to the title compound
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([NH+:7]([O-:35])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccncc1)c1ccc(OC(F)F)c2oc3ccccc3c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OC(F)F)c2oc3ccccc3c12)[NH+]([O-])c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A suspension of N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.14 mmol) (example 21) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.70 mmol) in chloroform (10 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was stirred in saturated sodium bicarbonate solution, filtered, dried and purified by column chromatography using 40% acetone-chloroform as the eluent to give 30 mg of N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=C/N(C)C)[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1)[CH:8]=[O:17]
Reactant: CN(C)/C=C/c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of (E)-2-(2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine (1.0 equiv) in 1:1 THF/H2O (0.1 M) was added sodium periodate (3.0 equiv) portionwise. The resulting solution was stirred at rt for 6 hours, at which time the white solid was filtered and rinsed with ethyl acetate. The entire filtrate was washed with NaHCO3(sat.), with NaCl(sat.), dried over MgSO4, filtered and concentrated. Purification by column chromatography (20% ethyl acetate/hexanes, Rf=0.3) yielded 2-chloro-5-nitroisonicotinaldehyde (71%). 1H NMR (CDCl3): δ 10.51 (s, 1H), 9.25 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2[nH]cnc2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 5-chloro-1H-benzo[d]imidazole (500 mg, 3.28 mmol) in 5 mL DMF, were added TEA (0.502 mL, 3.60 mmol) and TrCl (1.00 g, 3.60 mmol). The mixture was stirred at rt for 3 h, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes gradient) to afford 580 mg of 5-chloro-1-trityl-1H-benzo[d]imidazole, followed by 225 mg of 6-chloro-1-trityl-1H-benzo[d]imidazole (177.1) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][CH:11]([CH3:24])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[CH3:10][CH:11]([CH3:24])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(c1ccccc1)n1ccnc1
Agent: N
Agent: O=S(=O)(O)O
Product: CC(C)C(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
To a stirred and cooled (0° C.) amount of 55.2 parts of sulfuric acid were added portionwise 13 parts of 1-(2-methyl-1-phenylpropyl)-1H-imidazole mononitrate. After stirring for 1/2 hour at 0° C., the reaction mixture was poured into ice-water. The whole was basified with ammonia and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 12 parts (97.8%) of 1-[2-methyl-1-(4-nitrophenyl)-propyl]-1H-imidazole (interm. 40).
Reaction SMILES: [CH2:1]([C@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([Mg]Br)[CH3:25].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[CH2:1]([C@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:24][CH3:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC[Mg]Br
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C(O)CC)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)benzaldehyde (N) (16 mg, 0.05 mmol) in THF (0.2 mL) at 0° C. was added ethylmagnesium bromide (20 μL, 3M in THF) dropwise. After one hour, the reaction mixture was heated to refluxing temperature for an additional hour until TLC indicated completion of the reaction. Upon completion, saturated aqueous NH4Cl was added, and the mixture extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered and concentrated. Preparative thin layer chromatography (25% EtOAc/Hex, 250 μm, silica) yielded the title compound (6 mg, 0.017 mmol, 35%). 1H NMR (CDCl3, 300 MHz) δ 7.27 (2H, d, J=7.2 Hz), 7.21 (2H, d, J=8.1 Hz), 4.58 (1H, t, J=6.6 Hz), 3.88-3.81 (1H, m), 3.71-3.65 (1H, m), 2.92 (1H, dd, J=0.02, 18.6 Hz), 2.82 (1H, dd, J=0.02, 18.6 Hz), 1.86-1.68 (2H, m), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.92-0.85 (6H, m); HRMS (FAB+) calcd for C22H35O3 [M−H]: 347.2586; found 347.2575, C22H35O3.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH2:7]([O:23][C:24](Cl)=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)Cl>[CH2:7]([O:23][C:24]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=C(CO)CO
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(CO)COC(=O)OCCCCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 2.5 h

Procedure:
2-Methylenepropane-1,3-diol (5.0 g), hexadecyloxycarbonylchloride (17.4 g) and pyridine (4.4 g) was dissolved in methylene chloride (60 ml). The mixture was stirred for 2.5 hours at 22° C. The mixture was purified through a column of silica gel 60 (70-230 mesh, 30 g), eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®-System 500A using a PrepPAK®-500-SILICA cartridge with ether/chloroform/pentane 1:1:3 as eluent.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 78 %

Procedure:
As described for example 73c, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (95 mg, 78%) which was obtained as a light yellow foam. MS: m/e=394.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:12]3[S:13][CH:14]=[CH:15][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)=[N:10][N:11]3[CH:15]=[CH:14][S:13][C:12]=23)=[CH:22][CH:21]=1
Reactant: COc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
6-(3-Methoxy-phenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole (65 mg, 0.212 mmol) was dissolved in dry DCM (2 mL) and cooled to 0° C. A 1 M solution of boron tribromide in DCM (0.850 mL, 0.848 mmol, 4 eq) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 1 hours. Ice was then added to the reaction mixture, followed by saturated aqueous NaHCO3 until pH 6. The aqueous phase was extracted with DCM and the organic layer was dried and evaporated to dryness. An insoluble solid formed during extraction and it was filtered and combined with the organic layer. The crude product was taken up with toluene and concentrated to dryness three times and the same treatment was repeated with DCM. 50 mg of 3-(7-pyridin-4-yl-pyrazolo[5,1-b]thiazol-6-yl)-phenol (80%) were obtained as pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]#[CH:40].O>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]#[CH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (943 mg) and potassium carbonate (880 mg) in dimethylformamide (10 ml) was added propargyl bromide (0.2 ml) at room temperature. After 1 hour, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (5:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine (1.09 g) as an oil.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](O)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Trifluoromethanesulphonic anhydride (338 mg, 1.2 mmol) was added to a suspension of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, I mmol), (prepared as described for the starting material in Example 5), in methylene chloride (2 ml) containing pyridine (2 ml) cooled at 5° C. When the addition was complete, the mixture was left to warm to ambient temperature and stirred for 1 hour. After removal of the volatiles by evaporation, the residue was partitioned between ethyl acetate/ether and water. The organic layer was separated, washed with 0.5M hydrochloric acid, followed by water, brine, dried (MgSO4) and evaporated to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (400 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[OH:18][CH2:19][C:20]1[C:21](B(O)O)=[CH:22][S:23][CH:24]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:21]3[C:20]([CH2:19][OH:18])=[CH:24][S:23][CH:22]=3)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: OCc1cscc1B(O)O
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Product: Nc1nc2ccccc2n1-c1cccc(-c2cscc2CO)c1
Yield: 56 %

Procedure:
2-Amino-1-[3-(3-hydroxymethyl-4-thienyl)-phenyl]-benzimidazole was synthesized as above with amino-1-(3-iodophenyl)-benzimidazole and 4-hydroxymethyl-3-thienylboronic acid as starting materials. Yield 56%, mp. 106°-108° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]3[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=3[N:3]=2)=[C:28]([CH3:33])[CH:27]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(Br)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.00 g, 5.39 mmol), 4-bromo-2-methylaniline (3.01 g, 16.2 mmol), p-toluenesulfonic acid monohydrate (1.10 g, 5.78 mmol) and xylene (15 mL) was stirred at 150° C. for 20 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (2.11 g, 4.05 mmol, 75%).
Reaction SMILES: [C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2I)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:22]1([P:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CCOCC>[C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[P:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=N[C@H](c2ccccc2I)CO1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C1=N[C@H](c2ccccc2P(c2ccccc2)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 4a (94 mg, 0.286 mmol) in 4 mL ether was added t-BuLi (1.7 M solution, 0.34 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min before diphenylchlorophosphine (2.43 g, 11.0 mmol) was added slowly. The solution was allowed to warm to rt and was stirred overnight. Water was added. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 5a as a colorless oil (40%). [α]20D=−50.9 (c=2.0, CHCl3); 1H NMR (CD2Cl2, 360 MHz) δ 7.40-7.26 (m, 12H), 7.19 (dt, J=1.5 Hz, J=7.5 Hz, 1H), 6.93-6.89 (m, 1H), 5.82-5.75 (m, 1H), 4.24 (dd, J=is 8.4 Hz, J=10.2 Hz, 1H), 3.64 (dt, J=0.5 Hz, J=8.4 Hz, 1H), 1.28 (s, 9H); 13C NMR (CD2Cl2, 90 MHz) δ 175.8, 148.4 (d, J=24.0 Hz), 136.9 (d, J=10.2 Hz), 135.4-134.2 (m), 130.0-129.3 (m), 127.9 (br s), 126.8 (br s), 75.4 (d, J=4.4 Hz), 67.5 (m), 33.9, 28.3; 31P NMR (CD2Cl2, 145 MHz) δ-14.97; HRMS (M++1) m/z calculated for C25H27NOP 388.18248, found 388.17930.