Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](I)=[N:12][N:11]3[CH:17]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cl-].[Na+].O.O1CCCC1.C(OCC)(=O)C>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:17]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[N:12]=1
Reactant: O=C(CC1CC1)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
A mixture of 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (501 mg, 1.46 mmol), 3-aminophenol (479 mg, 4.39 mmol), potassium carbonate (807 mg, 5.84 mmol) and N,N-dimethylformamide (5 mL) was stirred at 120° C. for 12 hr. Tetrahydrofuran/ethyl acetate and saturated brine were added to the reaction mixture, and insoluble material was filtered off. The filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/80→0/100) to give the title compound (156 mg, 33%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([NH:18][C:19](=[O:36])[O:20][C@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28]CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C.[Pd]>[CH2:1]([NH:18][C:19](=[O:36])[O:20][C@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][OH:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@H]1CCCO[C@H]1CO

Procedure:
Following a procedure similar to that described in Preparation 4, but using a solution of 1.300 g of dl-cis-2-benzyloxymethyltetrahydropyran-3-yl N-heptadecylcarbamate (prepared as described in Preparation 65) in 30 ml of ethanol and 0.819 g of 10% w/w palladium on activated carbon, 0.977 g of the title compound was obtained as crystals. These crystals melted at 81.0°-82.0° C. after recrystallisation from diethyl ether.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:53][O:54][C:55]1[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[C:58]([O:64][CH3:65])[C:56]=1[NH2:57].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:57][C:56]2[C:58]([O:64][CH3:65])=[CH:59][C:60]([O:62][CH3:63])=[CH:61][C:55]=2[O:54][CH3:53])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)O)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)NCCCCCC(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCCCC(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 6-(4-methylbenzamido)hexanoic acid (498 mg, 2 mmol), o-phenylenediamine (216 mg, 2 mmol), EDCI (383 mg, 2 mmol), HOBt (405 mg, 3 mmol), and triethylamine (404 mg, 4 mmol) in dichloromethane (30 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by chromatography on silica gel to give the title compound (227 mg, 33.9%) as a white solid. 1H NMR (DMSO): δ 9.06 (s, 1H), 8.35 (s, 1H), 7.73 (d, J=3.0 Hz, 2H), 7.24 (d, J=3.0 Hz, 2H), 7.14 (1H, J=3.0, d), 6.86-6.89 (m, 1H), 6.70 (d, J=3.0 Hz, 1H), 6.50 (M, 1H), 4.80 (s, 2H), 3.22-3.26 (m, 2H), 2.30-2.35 (m, 5H), 1.53-1.65 (m, 4H), 1.36-1.38 (m, 2H). LC-MS: 340 (MH)+. purity>95%.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([S:23]([NH2:26])(=[O:24])=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (28.5 mg) in acetonitrile (5 mL) were added sodium iodide (22.9 mg) and chloro(trimethyl)silane (0.078 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (21.2 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:7]([C:9]1[S:13][C:12]([B:14]([OH:16])[OH:15])=[CH:11][CH:10]=1)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:9]1[S:13][C:12]([B:14]([OH:16])[OH:15])=[CH:11][CH:10]=1
Reactant: CC1CCCN1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1CCCN1Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
Batch 3: 2-Methylpyrrolidine (0.033 mL, 0.32 mmol) was added to a solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (1 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 2 h. NaCNBH3 (40 mg, 0.64 mol) was added, and stirring continued for 19 h. The reaction mixture was loaded directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH (12 mL) and a 2 M solution of NH3/MeOH (9 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHCO3 (2 mL) and extracted with EtOAc (3×2 mL) to give 7.8 mg of crude {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid. The crude boronic acid from the above three reactions were pooled and carried on for the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1H-indole-7-carboxamide (final weight after pooling the three batches of {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid was 19 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5].[C:33]([Mg]Br)#[CH:34]>C1COCC1.CCOCC>[CH3:31][C:7]1[C:6]([C:4](=[O:5])[C:33]#[CH:34])=[CH:30][N:9]2[C:8]=1[C:13]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=1)=[C:12]([C:28]#[N:29])[CH:11]=[N:10]2
Reactant: CON(C)C(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reactant: C#C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of amide from Example 417 (60 mg, 0.14 mmol) in THF (2 ml) at 0° C. was added ethynylmagnesium bromide (0.5 M in THF, 1.4 ml, 0.7 mmol). The reaction mixture was warmed to rt for 2 h, then heated at 50° C. for 2 h, and at rt overnight. Diluted with ether, washed with saturated NaHCO3, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (30 mg, 32%) (5% MeOH—CHCl3). It has a retention time of 6.82 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=393.2
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C@H:14]([CH2:34][C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:13]1)=[O:10])C1C=CC=CC=1>O1CCCC1>[C:9]([CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=2)[C@H:14]([CH2:34][C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 17 h
Yield: 52.5 %

Procedure:
A mixture of (2R)-4-(benzyloxycarbonylmethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazine (1.86 g), 10% Pd charcoal (0.186 g) and tetrahydrofuran (93 ml) was stirred for 17 hours under hydrogen gas atmosphere (1 atm). The catalyst was removed by filtration and the filtrate was concentrated. The residue was triturated with ethyl ether to give (2R)-4-(carboxymethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.83 g) as a white powder.
Reaction SMILES: [C:1]12([NH2:6])[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH2:7][C:8]1[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:7][C:8]1[CH:15]=[C:14]([NH:6][C:1]23[CH2:5][CH:3]([CH2:4]2)[CH2:2]3)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: NC12CC(C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc(N)cc1NC12CC(C1)C2
Temperature: 80 °C

Procedure:
A mixture of bicyclo[1.1.1]pentan-1-ylamine (201 mg, 1.68 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 230 mg, 1.68 mmol) and diisopropylethylamine (1.47 ml, 8.39 mmol) in DMA (3 ml) was heated at 80° C. in a septum sealed reaction vessel for 48 h. The reaction mixture was heated for 5 h at 120° C. and 18 h at 80° C., then cooled, evaporated and purified twice by normal phase chromatography using 24 g RediSep® columns, eluting with gradients from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Cs+].Br[CH2:25][CH:26]=[C:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:1]1([C:7](=[N:8][CH:9]([CH2:25][CH:26]=[C:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCC=C1CCOCC1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CC=C1CCOCC1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl N-(diphenylmethylidene)glycinate (5.29 g, 19.8 mmol), benzyltriethylammonium chloride (0.41 g, 1.8 mmol) and cesium hydroxide monohydrate (4.54 g, 27.0 mmol) in anhydrous dichloromethane (50 mL) was added 4-(2-bromoethylidene)tetrahydro-2H-pyran (3.44 g, 18.0 mmol) as a solution in anhydrous dichloromethane (40 mL) and the reaction stirred at room temperature for 72 h under nitrogen. The reaction was partitioned between dichloromethane and water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-40% hexanes/EtOAc to afford the title compound as a clear oil in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.N.[Li]>C1COCC1.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][C@@H:11]([CH3:22])[C@@H:12]1[OH:21]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]12
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]32)C1
Temperature: -40 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A solution of 10.0 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17β-ol in 200 ml of absolute THF and 20 ml of tert.-butanol is dropped at -50° C. to about 500 ml of ammonia and then combined in incremental portions with 6.3 g of lithium. The mixture is agitated for 3 hours at -40° C., ammonia is allowed to evaporate overnight, the residue is taken up in about 1 liter of water, and extracted with ethyl acetate, thus obtaining 9.6 g of 3-methoxy-16α-methyl-2,5(10)-estradien-17β-ol as an amorphous crude product which is used in the subsequent stage without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](OS(C(F)(F)F)(=O)=O)([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:5][CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNC(OS(=O)(=O)C(F)(F)F)(c2cnc3ccccc3c2)c2ccccc21
Solvent: Cc1ccccc1
Product: CC1(C)CCN=C(c2cnc3ccccc3c2)c2ccccc21
Temperature: 25 °C
Yield: 12.8 %

Procedure:
3-Quinoline boronic acid triol salt (compound no. C2-12) (0.46 g, 1.56 mmol) synthesized by the method of Example 9, trifluoromethanesulfonic acid 5,5-dimethyl-1-(3-quinolinyl)-4,5-dihydro-3H-2-benzazepin-1-yl ester (0.5 g, 1.56 mmol) and tetrakistriphenyl phosphine palladium (0.86 g, 0.31 mmol) were added to 5 mL of toluene. After sparging with nitrogen gas, the resulting reaction solution was heated to reflux, and maintained for 14 hours. Then the reaction solution was cooled to room temperature and poured into ice water, followed by extracting with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to obtain the target compound (0.06 g, yield: 13%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CC1N=C(N2CCC(=CC#C)CC2)C([N+]([O-])=O)=CC=1.C[Si](C)(C)C#CC=C1CCNCC1.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56](Br)[N:55]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Br:53][C:54]1[N:55]=[C:56]([C:3]#[C:4][CH:5]=[C:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#C[Si](C)(C)C)CC1
Reactant: Brc1cccc(Br)n1
Agent: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cccc(Br)n2)CC1
Yield: 68 %

Procedure:
The title compound was prepared from Compound 2a (in place of Compound 274c) following the procedure described for the compound of Example 274, using 2,6-dibromopyridine instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 10:0 to 8:2 affording the title product. White solid. Yield: 68%.
Reaction SMILES: [Br:1][C:2]1(Br)[CH:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]1=[O:15].N12CCCN=C1CCCCC2>CC#N>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15]
Reactant: COc1ccc2c(c1)CC(C)C(Br)(Br)C2=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(O)c(Br)c(C)cc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101 %

Procedure:
This compound was prepared according to procedures described for similar compounds (i.e. 2-bromo-1-naphthols) as reported by G. R. Green et. al. (Tetrahedron, (1998), 54, 9875-9894), with modification. To a stirred solution of 3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone (12) (4.80 g, 25.2 mmol) in CHCl3 (130 mL) was slowly added dropwise a solution of Br2 (8.12 g, 50.81 mmol, 2.02 eq) in CHCl3 (60 mL) over a period of 4 h at RT under N2. The reaction mixture was stirred overnight. The reaction mixture was concentrated to give 9.82 g of crude 2,2-dibromo-3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone as a dark brown-orange oil [1H NMR (400 MHz; CDCl3): δ 1.49 (d, J=6.3 Hz, 3H), 2.56 (m, 1H), 2.91 (m, 2H), 3.86 (s, 3H), 6.67 (d, J=2.2 Hz, 1H), 6.90 (dd, J=2.5 Hz, 8.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H)]. A solution of 2,2-dibromo-3-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-naphthalenone (9.8 g, 25.2 mmol) in CH3CN (160 mL) was cooled in an ice-water bath to 0-5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6 mL, 6.11 g, 39.6 mmol, 1.57 eq) was added slowly dropwise under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT under N2 for 40 min. To the reaction mixture was added 1 N HCl (160 mL) and the aqueous mixture was extracted with CH2Cl2 (2×). The organic extracts were combined, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give 6.8 g (100%) of the title compound 13 as a solid. 1H NMR (400 MHz; d6-DMSO-d6): δ 2.43 (s, 3H), 3.83 (s, 3H), 7.07 (dd, J=2.2 Hz, 9.2 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.29 (s, 1H), 8.04 (d, J=9.1 Hz, 1H), 9.66 (s, 1H).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:34]1
Reactant: NNc1cc(F)ccc1F
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cc(F)ccc3F)c3cc(O)ccc23)c(O)c1
Yield: 18.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.4 g, 1.6 mmol), sodium acetate (0.27 g, 3 mmol) and 2,5-difluorophenylhydrazine hydrochloride (0.45 g, 3 mmol) to give 0.107 g of product as an off-white colored solid.
Reaction SMILES: O[C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.CCN(S(F)(F)[F:18])CC>C(Cl)Cl>[F:18][C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1CC(C)(O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC(C)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 3-hydroxy-3-methylcyclobutanecarboxylate (500 mg, 3.16 mmol) in DCM (5 mL) was added DAST (0.626 mL, 4.74 mmol) at −78° C. and the reaction mixture was slowly allowed to warm to RT and stir for 3 h. The reaction mixture was diluted with DCM (25 mL), washed with H2O and a saturated aq. solution of NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 25% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 288A as a pale yellow liquid (0.2 g, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.08 (q, J=7.0 Hz, 2H), 3.22-3.09 (m, 1H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.22-1.11 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[NH2:43][C:44]1[N:49]=[CH:48][C:47](Br)=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[N:49]=[CH:48][C:47]([C:31]2[CH:32]=[CH:33][C:28]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:30]=2)=[CH:46][N:45]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]-pyrimidin-4-one (prepared as described in example 51, 0.90 g, 1.5 mmol) in N,N-dimethylformamide (25 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyrimidine (0.388 g, 2.23 mmol), cesium carbonate (0.97 g, 2.98 mmol), Pd(dppf)2Cl2 (0.109 g, 0.149 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 4 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography over silica gel (60-120 mesh) to afford 6-[4-(2-amino-pyrimidin-5-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (T-468). 1H NMR (CDCl3, 400 MHz) δ 8.95 (s, 1H), 8.57 (br, 3H), 8.37 (s, 1H), 7.93 (d, 1H), 7.74 (m, 1H), 7.37-7.51 m, 6H), 7.16 (d, 2H), 5.31 (br, 2H), 3.13 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 570.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17]C(=O)C)[N:3]=1.N>Cl.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH2:17])[N:3]=1
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reaction time: 1.75 h

Procedure:
A suspension of 2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (2.97 g, 8.96×10−3 mole) in 12M hydrochloric acid (1.31 ml) and water (4.04 ml) was fluxed for 1.75 hrs. The cooled mixture was then basified with 0.880 aqueous ammonia (5 ml) and extracted with chloroform (3×50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo at 80° C. Yield 2.29 g (88%), M.p. 178-180° C.