Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[CH3:27][O:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][N:30]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]([O:28][CH3:27])=[N:30]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: COc1n[nH]c2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccccc12
Temperature: 125 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 μmol), 3-methoxy-1H-indazole (50.1 mg, 338 μmol) in dioxane (2 mL) was added sodium tert-butoxide (71.5 mg, 744 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.3 mg, 33.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, and the filter cake washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the crude residue purified by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (138 mg, 80%).
Reaction SMILES: Cl[CH2:2][CH:3]1[S:11][C:10]2[N:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][CH3:15])[C:8](=[O:12])[CH:9]=2)[CH2:4]1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(Cl)Cl.O>[C:17]1([S:23][CH2:2][CH:3]2[S:11][C:10]3[N:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][CH3:15])[C:8](=[O:12])[CH:9]=3)[CH2:4]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)cc2n(c1=O)CC(CSc1ccccc1)S2
Yield: 95 %

Procedure:
A mixture of 2-chloromethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (0.8 g), thiophenol (0.47 ml) and potassium carbonate (0.63 g) was refluxed in ethanol (20 ml) for 42 hours. The solution was concentrated to dryness, and the resulting residue thus obtained was dissolved in methylene chloride and water. After washing with water and drying, the organic solution was concentrated to dryness. The resulting syrup was purified by column chromatography on silica gel to give colorless syrup. This syrup was allowed to stand in a refrigerator to obtain colorless crystals (1.2 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])S(C2C=CC=CC=2)(=O)=O)=[C:4]([CH3:19])[CH:3]=1.[Li]C(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(O)(C(F)(F)F)=O>C1COCC1>[F:25][C:26]([F:35])([F:36])[C:27]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:18])=[C:4]([CH3:19])[CH:3]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]
Reactant: Cc1cc(Br)ccc1N(C)S(=O)(=O)c1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C(O)(c2ccccc2)C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.03 g (3.23 mmol) of N-(4-bromo-2-methylphenyl)-N-methyl-benzenesulfonamide in 30 ml THF at −78° C. was added dropwise 3.9 ml (6.63 mmol) of a 1.7M solution of tert-BuLi in hexanes and the resultant mixture was stirred at −78° C. for 0.5 h. To this mixture was then added 0.66 ml (4.7 mmol) of 2,2,2-trifluoroacetophenone and the mixture stirred at −78° C. for an additional 0.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. 253 mg (0.61 mmol) of this material and 3 ml of TFA was heated to 50° C. for 4 hours. After this time, excess TFA was removed in vacuo, water was added and the mixture was neutralized by the addition of a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc and combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 3:1) to give the title compound. 1H-NMR (CDCl3) δ 2.12 (s, 3H), 2.92 (s, 3H), 6.57 (d, J=8.5 Hz, 1H), 7.16 (s, 1H), 7.16 (brs, 1H), 7.37-7.41 (m, 3H), 7.54-7.56 (m, 2H). Mass Spectrum (CI+) m/e=296.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:12][C:13](=O)[C:14]3[NH:15][CH:16]=[N:17][C:18]=3[N:19]=2)=[CH:6][N:5]=1)[CH3:2].S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+].[OH-].[NH4+]>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([NH:15][CH:16]=[N:17]3)=[C:13]([Cl:23])[N:12]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cn1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Nc2nc(Cl)c3[nH]cnc3n2)cn1
Temperature: 0 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
A mixture of N2-(2-Ethoxypyridin-5-yl)guanine (6.35 g; 23.3 mmol) and N,N-dimethylformamide (70 mL) is cooled to 0° C. and treated dropwise with thionyl chloride (5.6 mL; 76.8 mmol). An additional 15 ml of N,N-dimethylformamide is added and the mixture is heated at 50° C. for 1 h. The reaction mixture is cooled to room temperature and poured slowly into a solution of sodium bicarbonate (8 g) in water (80 mL). The pH is adjusted to 6 with saturated aqueous sodium bicarbonate solution and the mixture is chilled overnight. The precipitate is collected by filtration and washed with water and methanol to give a brown solid which is dissolved in warm concentrated ammonium hydroxide (30 mL) and allowed to stand at room temperature for 3 days. The precipitate is collected by filtration and washed with water and methanol to afford 2-[(2-Ethoxypyrid-5-yl)amino]-6-chloropurine (4.72 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:19]3[C:14]([CH:13]=2)=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:27]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cc1ccccc1O
Product: COc1ccc2c(Oc3ccccc3C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-methyl-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-o-tolyloxy-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Product: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Yield: 23 %

Procedure:
Following General Procedure B1, 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (0.244 g, 0.80 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.156 g, 0.87 mmol) to afford the title compound (0.066 g, 33%) as a colorless oil. MW=358.74. 1H NMR (CDCl3, 500 MHz) δ 7.37-7.31 (m, 2H), 7.17-7.12 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.43 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), 1.32-1.25 (m, 3H); APCI MS m/z 359 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.O1CCCC1>CO>[OH:15][CH2:14][C:11]1([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2cccnc2)CC1
Temperature: 0 °C

Procedure:
A flask was charged with 1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic acid (4.0 g, 13.1 mmol) and tetrahydrofuran (25 mL). The reaction was placed under nitrogen. To the flask was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 26.1 mL, 26.1 mmol) and heated at reflux for 2 h. The reaction was cooled to 0° C. and quenched with methanol (100 mL). The solution was then concentrated in vacuo. The residue was purified via column chromatography (5% methanol/95% dichloromethane) to yield 3.2 g (84%). Mass Spec.: 293.26 (MH)+. LC: tr=1.65 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:12])[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4]>C1COCC1.[OH-].[Li+].CO>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[C:11]([NH:10][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH:7]=[CH:8][CH2:9]2)=[O:12])=[CH:30][CH:29]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CC=CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CC=CC1)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 65.2 %

Procedure:
316 mg 1-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid methyl ester in 9 ml THF, 1.6 ml of 2 M lithium hydroxide and 18 ml methanol were reacted at room temperature for 8 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 200 mg of 1-{[1-(4-trifluoromethyl-benzyl-oxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@H](O)c1ccccc1
Yield: 91.2 %

Procedure:
A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml (628 mmol) of benzyl alcohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700 ml of benzene was refluxed for 6.5 hours. The mixture was washed with water and concentrated. The residue was recrystallized from ether to give 123.5 g of the aimed compound D-2 in 91% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(OCC)(=O)C.[Pd]>[C:4]1([C:5]2[O:1][C:2]3[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:10]=[CH:11][CH:12]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reaction time: 5 h
Yield: 159.8 %

Procedure:
To a solution of ethyl 3-hydroxy-4-nitrobenzoate (3.56 g) in ethyl acetate (100 mL) was added 10% palladium/carbon (600 mg), and the mixture was stirred under hydrogen atmosphere for 5 hr. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the residue in methanol (100 mL) were added benzaldehyde (1.50 mL) and sodium sulfate (1.00 g), and the mixture was stirred at 45° C. for 16 hr. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the residue in methylene chloride (100 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (4.21 g), and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution (300 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL×2). The organic layer was washed with saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (3.60 g) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].[C:29]([CH2:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N1CCOCC1)C.C(Cl)CCl>CN(C)C=O>[CH:17]1([CH2:16][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([CH2:35][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:23][C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CCN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of 880 mg (2.23 mmol) of (S)-α-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide, 608 mg (2.45 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0 184 550), 0.35 ml (2.76 mmol) of 4-ethylmorpholine, 662 mg (4.9 mmol) of HBT and 529 mg (2.76 mmol) of EDC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is poured into a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulphate the solvent is evaporated under reduced pressure and the residue (1.01 g), for purification, is chromatographed on 70 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/methanol/ether yields 900 mg of (S)-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, melting point 160°, MS: 624 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][N+:11]([O-:13])=[O:12].[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:10][N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(C[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3-bromobenzaldehyde (18.5 g, 100 mmol) in MeOH (100 mL) was added MeNO2 (12.2 g, 200 mmol) at 0° C. followed by addition of KOH (11.2 g, 200 mmol). After 2 hours, MeOH was removed in vacuo and the resulting mixture was partitioned between ethyl acetate and water. Ethyl acetate extracts were dried over MgSO4 and concentrated to give 20 g crude mixture. This crude mixture was dissolved in AcOH (200 mL), to which CrO3 (12.0 g, 120 mmol) was added. Acetic acid was removed under vacuo after 2 hours and water (200 mL) was added and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and then concentrated under vacuo. dichloromethane (20 mL) was added and the titled compound (8.5 g, 35% for 2 steps) was precipitated out and collected by filtration.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)[S:61][C:51]=2[C:52]([N:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(N4CCOCC4)c3)nc12

Procedure:
From 3-morpholin-4-yl-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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:8][C:4]1[N:3]=[C:2]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of 2,6-dibromopyridine (2.07 g, 8.7 mmol), 2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzonitrile (prepared as described in Tetrahedron (2001), 57(49), 9813-9816, 3.00 g, 13 mmol) and potassium phosphate (3.71 g, 17 mmol) in DMF (40 mL) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (303 mg, 0.26 mmol) was added, the mixture was degassed as before, and was then stirred at 80° C. under nitrogen overnight. The mixture was partitioned between water and ethyl acetate, and the resulting aqueous layer was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with water (1×100 mL) and saturated sodium chloride solution (1×100 mL), then were dried over magnesium sulfate and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate in isohexane, affording 2-(6-bromopyridin-2-yl)benzonitrile as a solid (680 mg, 30%). δH (400 MHz, CDCl3) 7.51-7.57 (2H, m), 7.68-7.73 (2H, m), 7.80 (2H, d, J 7.7), 7.91 (1H, dd, J 0.7 and 7.7).
Reaction SMILES: CS(C1C=CC(CCC)=C(C=1)N)(=O)=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:31]([O-])=O.CS(C1C=CC(Br)=CC=1)(=O)=O>CO.CCOC(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[NH2:31]
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: CCCc1ccc(S(C)(=O)=O)cc1N
Agent: CS(=O)(=O)c1ccc(Br)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1N
Yield: 94 %

Procedure:
Following the general method as outlined in Intermediate 61 using MeOH and EtOAc as solvents, starting from 1-methyl-2-nitro-4-(phenylsulfonyl)benzene (Intermediate 112) and 4-bromophenyl methyl sulfone, the title compound was obtained as a beige solid in 94% yield.
Reaction SMILES: CN(C=O)C.[C:6]([C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[C:19][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]4)=[N:35][CH:36]=3)[N:21]=2)[CH2:11][CH2:10]1)(=[O:8])[NH2:7]>[Pd].CCN(CC)CC>[C:6]([C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:41][CH2:42]4)=[N:35][CH:36]=3)[N:21]=2)[CH2:11][CH2:10]1)(=[O:8])[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Reaction time: 20 h

Procedure:
DMF (3 mL) and Et3N (0.30 mL) were added to a mixture of tert-butyl 4-(5-((4-((2-(1-carbamoylcyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A78 (0.118 g, 0.194 mmol) and 10% Pd/C (0.182 g). The mixture was stirred under a hydrogen atmosphere for 20 hours, filtered through Celite and the filtrate concentrated under reduced pressure. Purification by silica gel column chromatography (0-100% EtOAc in Petroleum Benzine 40-60° C.) gave the title compound A79 (0.080 g, 67%). LCMS-A: rt 5.852 min; m/z 611.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].BrC(C)(C)C([O-])=O>C(C(C)=O)C>[CH3:40][C:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(Cl)cc1C(=O)NCc1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)(Br)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Reaction time: 3 h

Procedure:
2.7 gm (7.35 millimols) of 4-[2-methoxy-5-chlorobenzamido-methyl]-4'-hydroxy-biphenyl were refluxed in 30 ml of methyl ethyl ketone with 1.26 gm (9.2 millimols) of potassium carbonate for 1 to 2 hours, and then 2.23 gm (11 millimols) of ethyl 2-bromo-2-methyl-propionate were added dropwise. After three hours, another 0.63 gm (4.6 millimols) of potassium carbonate and 0.46 gm (2.2 millimols) of 2-bromo-2-methyl-propionate were added to complete the reaction, and the mixture was heated for 3 to 4 hours more. After cooling, filtering and distilling off the solvent, the residual crude product was purified by chromatography on a silicagel column with benzene/ethyl acetate (9:1) as the eluant. The evaluation of column chromatograph was carried out by thin-layer chromatography. The fractions containing the pure product were combined, and the solvent was distilled off, yielding 1.8 gm (51% of theory) of a slightly yellow oil. M.p. < 20° C.