Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 32 %

Procedure:
5.0 g (12.2 mmol) of 1-benzyl-7-benzyloxy-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 9 ml (14.7 mmol) of a 15% strength solution of n-butyllithium in hexane and 2.4 ml (29.4 mmol) of dimethylformamide are reacted in 125 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 32%, m.p.: 147°-149° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[CH:17][N:18]4C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.C[O-].[Na+]>CO>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:4]1[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[CH:17][NH:18]4)=[CH:14][CH:13]=3)[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Cn3nnc4c(-c5ccco5)nc(N)nc43)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccc4cc[nH]c4c3)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 6.7 %

Procedure:
A mixture of tert-butyl 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-ylmethyl)indole-1-carboxylate (135 mg, 4.08 mmol), and NaOMe (22 mg, 4.08 mmol) in MeOH (10 mL) was refluxed for 1 h, treated with NaOMe (110 mg, 20.4 mmol), refluxed for a further 4 h then stirred at room temperature for 17 h. The mixture was concentrated in vacuo to half volume and the resulting precipitate was filtered and washed with H2O to give the title compound (90 mg, 96%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:52]=[CH:51][C:5]([CH2:6][C@@H:7]([NH:32][CH2:33][C@H:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][N:35]2C(OC(C)(C)C)=O)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([C:8]([N:10]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:12]3)=[O:9])[NH:32][CH2:33][C@H:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][NH:35]2)=[CH:51][CH:52]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
0.29 g of tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]-amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate is placed in 1.1 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred at ambient temperature for 1 h. After hydrolysis with a 1N aqueous sodium hydroxide solution, extraction is carried out with dichloromethane until the aqueous phase is completely depleted. Drying over MgSO4 and concentration to dryness are carried out. The crude obtained is chromatographed on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and methanol. 0.12 g of N-(8-{4-chloro-N-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-D-phenylalanyl}-8-azabicyclo[3.2.1]oct-3-yl)-N-cyclohexyl-N′,N′-diethylurea is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH2:4][CH2:5][Se]C1C=CC=CC=1[N+]([O-])=O.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH:4]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC[Se]c4ccccc4[N+](=O)[O-])C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of racemic N-(4,4-dimethyl-1-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 g of 77%, 1.79 mmol). After stirring for 1 hour at room temperature, the mixture was diluted with dichloromethane (100 mL) and the resulting solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes) to afford 623 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 496.76.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)[CH3:2].Cl.[NH2:15][OH:16]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Ethoxypropyl)-4piperidone oxime is prepared from 1-(3-ethoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][C@H:6]([C:13]([OH:15])=[O:14])[CH2:5]2.Cl.[CH3:17]O>>[CH3:17][O:14][C:13]([C@@H:6]1[CH2:5][C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)[CH2:8][NH:7]1)=[O:15]
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 18 h

Procedure:
(S)-6,7-Dihydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (62 g), 200 mL anhydrous MeOH, and 26 mL concentrated hydrochloric acid were stirred together overnight at 70° C. The mixture was then evaporated and the residue resuspended in 500 mL acetonitrile with vigorous stirring to wash all the solid material. Stirring continued for 18 h at r.t., after which the solid product was collected by filtration, washed with 100 mL acetonitrile, and dried under vacuum overnight. Yield 77 g (quantitative). 1H NMR (400 MHz, MeOH-d4): 6.64(s, 1H), 6.61(s, 1H), 4.42-4.36(m, 1H), 4.29-4.24(m, 2H), 3.89(s, 3H), 3.29-3.22(m, 1H), 3.11-3.02(m, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC([N:16]=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH2:16])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To compound L (250 mg, 0.598 mmol) in CH2Cl2 (8 mL) was added benzoic acid (100 mg, 0.819 mmol), DCC (200 mg, 0.971 mmol), and DMAP (10 mg, 0.082 mmol) at room temperature. A heterogeneous mixture resulted after approximately 5 minutes and stirring was continued for an additional 3 hours. The contents were concentrated in vacuo and chromatographed on SiO2 (3% acetone-CH2Cl2) which afforded the benzamide contaminated with residual Ph3P. Repeated recrystallization of this material from Et2O afforded 198 mg (63%) of compound M as a pale off white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[CH3:23][O:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=[C:27]([NH2:40])[N:26]=1>>[CH3:23][O:24][C:25]1[C:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:5]=[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:29][N:28]=[C:27]([NH2:40])[N:26]=1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Nc2cc(N3CCOCC3)nc(Cl)n2)cn1
Product: COc1ccc(Nc2cc(N3CCOCC3)nc(-c3cnc(N)nc3OC)n2)cn1

Procedure:
According to Example 1, the reaction of 2-chloro-N-(6-methoxypyridin-3-yl)-6-morpholinopyrimidin-4-amine (40 mg, 0.124 mmol) with 4-methoxy-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (94 mg, 0.372 mmol) gave 4′-methoxy-N4-(6-methoxypyridin-3-yl)-6-morpholino-2,5′-bipyrimidine-2′,4-diamine. A mixture of crude 4′-methoxy-N4-(6-methoxypyridin-3-yl)-6-morpholino-2,5′-bipyrimidine-2′,4-diamine and morpholine (0.108 mL, 1.24 mmol) in N-methylpyrrolidinone (2 mL) was heated under microwave irradiation (high absorption, fixed hold time) for 20 minutes at 200° C. Additional morpholine (0.108 mL, 1.24 mmol) was added and the solution heated at 200° C. under microwave irradiation for another 50 minutes. Another portion of morpholine (0.108 mL, 1.24 mmol) was added and the mixture heated at 200° C. under microwave irradiation for 90 minutes. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the bis-TFA salt of 2-amino-5-(4-(6-methoxypyridin-3-ylamino)-6-morpholinopyrimidin-2-yl)pyrimidin-4(3H)-one was isolated as an off white solid (24.6 mg, 50%): LCMS (m/z): 397.1 (MH+). Rt: 1.92 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][N:28](C3CCCCO3)[C:22]=2[CH:21]=1.[CH3:36][N:37]([CH3:58])[C:38]([CH:40]1[CH2:44][C:43]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:42]=2[O:41]1)=[O:39]>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:46]3[CH:47]=[CH:48][C:42]4[O:41][CH:40]([C:38]([N:37]([CH3:36])[CH3:58])=[O:39])[CH2:44][C:43]=4[CH:45]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)c3cn2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 83 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Example 52, Step 5) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)+=481.0.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O.CO>O1CCCC1.[C].[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(C)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of methyl 5-methyl-4-nitrothiophene-2-carboxylate (95 g) and 10% palladium-carbon (50% containing water, 10 g) in tetrahydrofuran (250 mL)-methanol (250 mL) was stirred at 50° C. for 8 hr under a hydrogen atmosphere (0.3 MPa). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give methyl 4-amino-5-methylthiophene-2-carboxylate (58 g, yield 72%) as yellow crystals. melting point 91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=O)[NH:8][SH:9](=[O:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.O.P(Cl)(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][C:7]1[NH:8][SH:9](=[O:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=2[N:6]=1
Reactant: O=C1Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[SH]1(c2ccccc2)NC(Cl)=Nc2ccc(Cl)cc21

Procedure:
A suspension of 2.92 g (0.01 mole) of 7-chloro-1-phenyl-1,2,4-benzothiadiazin-3(4H)-one-1-oxide in 25 ml of phosphorus oxychloride is treated with 0.5 ml of water and the mixture is heated under reflux for 45 minutes. The solution is then cooled and poured into 100 ml of a mixture of ice and water. The soluble oily material is taken up in chloroform, the chloroform solution dried, filtered, concentrated, and the residual material recrystallized from acetonitrile to give 0.85 g of colorless product, melting point 162°-164°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:14])[CH:10]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:9]1)=[O:7].[C-:35]#[N:36].[K+]>CN(C=O)C>[Cl:34][C:29]1[CH:28]=[C:27]([CH:10]2[CH:11]([N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=3)[CH3:14])[CH2:12][N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:35]#[N:36])[CH2:9]2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: [C-]#N
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCBr)CC1c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCC#N)CC1c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a stirred solution of 5-bromo-1-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-pyrrolidin-1-yl}-pentan-1-one (XV-1) (40 mg, 0.068 mmol) in DMF (2 ml) was added potassium cyanide (5.0 mg, 0.077 mmol) and 18 crown 6-ether (18 mg, 0.068 mmol). The reaction mixture was stirred at 40° C. overnight, concentrated under vacuo. The product was purified by preparation HPLC to yield 3.2 mg (9%) of the title product as a colorless oil. ES-MS m/e: 530.1 (M+H+).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].C[Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)([OH:19])[C:2]([F:4])([F:3])[F:1])=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C[Si](C)(C)Oc1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(O)(c2ccc(Br)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ed) 4 ml of trifluoromethyltrimethylsilane are added to a a solution of 3.1 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 60 ml of THF at 0° C. under argon. After stirring at 0° C. for 30 min. 69.3 ml of 1M tetrabutylammonium fluoride solution in THF are added dropwise. The reaction mixture is warmed to room temperature and stirred, subsequently treated with 40 ml of water, again stirred and then extracted with methylene chloride. The extracts are washed with saturated sodium chloride solution, dried and evaporated. The crude product is purified over silica gel with toluene/acetone (98:2) as the eluent. 3.0 g of (RS)4-[1-(4-bromo-phenyl)-2,2,2-trifluoro-1-hydroxyl-ethyl]-phenol, MS: m/e 290 (M-CO, 1Br), are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:14]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH2:12]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1C(C)(C)C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of o-(t-butyl)-phenol (11.3 g; 75 mmol) in acetone (150 ml) is added allyl bromide (10.9 g, 1.2 equiv.) and anhydrous K2CO3. After stirring 18 hr at reflux, the reaction is added to water (200 ml) and extracted with 3×150 ml portions of petroleum ether. The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel (sg) chromatography (hexane elution) to yield 1-prop-2-enyloxy-2-t-butylbenzene (11.6 g; 81% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(O)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl) propionic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours and the sieves were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3×100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80%) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 73.1 %

Procedure:
3-Iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 0.754 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (290 mg, 0.829 mmol), palladium tetrakistriphenyphosphine (52 mg, 0.045 mmol) and sodium carbonate (192 mg, 1.81 mmol) were mixed in ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give tert-butyl N-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (250 mg, 73%). 1H NMR (DMSO-d6) δ 1.48 (s, 9H), 1.88 (m, 2H), 2.10 (m, 2H), 2.24 (m, 5H), 2.92 (m, 2H), 3.69 (s, 3H), 4.64 (m, 1H), 7.21 (m, 2H), 7.91 (d, J=8.16 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=454.2, Rt=1.67 min.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[C:14]([NH2:17])(=[S:16])[CH3:15].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:16][C:14]([CH3:15])=[N:17][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(N)=S
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(C)c(-c2ccc(C#N)cc2)s1
Temperature: 100 °C

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (0.9 g, 3.83 mmol) in toluene (2 ml) was treated with thioacetamide (0.6 g, 8 mmol) followed by pyridine (0.45 ml). The mixture was warmed to 100° C. for 1 hour, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and evaporated to a yellow oil. Chromatography on silica gel, eluting with 5% ether in dichloromethane, afforded a pale yellow oil which crystallised (0.52 g, 64%), m.p. 108°-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=[O:19].[Na+].[Na+].OO>C(O)C.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:19])[NH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(C#N)c2c1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C

Procedure:
To 213 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 6 mL of ethanol and 6 mL of DMSO was added 3 mL of Na2CO3 (3M), followed by 3 mL of H2O2 (30% in water). After 24 h of reaction, the mixture was worked up to give 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 7.4 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.7 (s, 1 H) 7.8 (m, 1 H) 8.0 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]>>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Fc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromofluorobenzene. MS (ESI): mass calcd. for C16H11F2N3, 283.09; m/z found, 284.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.63-8.54 (m, 1H), 8.13 (d, J=1.4, 1H), 8.00 (m, 1H), 7.52-7.31 (m, 4H), 7.24-7.12 (m, 2H), 4.72 (s, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([O-])=O.O>CS(C)=O>[O:7]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccc2)s1
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
Phenol (3.3 g, 35 mmol) is added in portions to a suspension of 60% NaH (1.3 g, 35 mmol) in DMSO (100 mL). The resulting mixture is stirred for 30 min then 5-nitrothiophene-2-carboxaldehyde (5 g, 32 mmol) is added. After 1 hr the reaction mixture is poured into water (1L) and washed with ether (4×500 mL). The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness. The resulting material is dissolved in MeOH and passed through a column (2.5 cm×20 cm) of Amberjet 4400 (OH− form). The eluent is dried in vacuo then evaporated twice from CH3CN. The crude product is purified by column chromatography in EtOAc-hexanes (1:1) to yield 5-phenoxy-thiophene-2-carboxaldehyde (304 mg, 5%). 1H NMR (300 MHz, CDCl3) δ 6.52, 7.20, 7.27, 7.45, 7.55, 9.75.