Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.CC1C=C([N+:29]([O-])=O)C=CC=1C(O)=O>>[NH2:29][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[C:8](=[O:11])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1=O
Product: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C1=O

Procedure:
tert-Butyl 5-amino-1-oxoisoindoline-2-carboxylate was prepared following the same procedure used for the preparation of tert-butyl 6-amino-1-oxoisoindoline-2-carboxylate using 2-methyl-4-nitrobenzoic acid as starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.C(OCC)C>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cccnc2)cc1
Reaction time: 3.5 h
Yield: 95.4 %

Procedure:
A solution of 3-(4-nitrophenoxy)pyridine (5.00 g, 23.13 mmol) in EtOAc (100 mL) in a 250 ml Parr bottle was purged with nitrogen. To this solution was added EtOAc-moistened 10% Pd/C catalyst (500 mg, 10% by weight). The reaction flask was placed in a Parr hygrogenation apparatus, purged with nitrogen (5×), evacuated, and then pressurized to 40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was then purged with nitrogen, and filtered through a pad of Celite®, rinsing with ethyl acetate (3×) and ethanol (3×). The filtrate was evaporated at reduced pressure to give a brown crystalline residue. The residue was stirred in diethyl ether at room temperature for 16 h and then filtered to provide 4.11 g (95%) of the desired product as light brown crystals. 1H-NMR (DMSO-d6) δ 8.21 (m, 2H), 7.30 (ddd, J=8.4, 4.6, 0.7 Hz, 1H), 7.18 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 5.05 (br s, 2H); MS LC-MS [M+H]+=187, RT=1.03 min.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:10]=2[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1([C:9]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:10]=2[CH2:11][OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A solution of (2-(1-methoxycyclohexyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (61 mg, 0.15 mmol) and tetrabutylammonium fluoride (0.2 mL; 0.2 mmol; 1.0M in tetrahydrofuran) was stirred in tetrahydrofuran (1 mL). The reaction was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was purified by 4 g RediSep column (Teledyne Isco inc., Lincoln Nebr.) (eluted with 10-40% ethyl acetate in heptane) to give 30 mg (69% yield) of a colorless gum. MS-GC (El): Calc: 288.3, Found: 288 (M). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (s, 1H), 7.50 (d, J=8.30 Hz, 1H), 7.41 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 2.99 (s, 3H), 2.24 (d, J=13.28 Hz, 2H), 1.8-1.57 (m, 7H), 1.28 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6](OC(C)C)=[O:7].[NH3:33]>O1CCOCC1>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([NH2:33])=[O:7]
Reactant: N
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Solvent: C1COCCO1
Product: NC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a mixture of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (1.0 g, 2.24 mmol, 1.0 eq) in dioxane (10 mL) was added NH3 (35% aqueous solution, 30 mL). The reaction was then heated to 100° C. and stirred overnight. The resulting mixture was concentrated in vacuo. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (320 mg, 36%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH3:16]>CN(C)C=O>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH3:16]
Reactant: OCC1CCCNC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of piperidin-3-ylmethanol (3.88 g) in dimethylformamide (50 mL) was added potassium carbonate (9.3 g) and ethyl bromide (2.52 mL). The reaction was stirred overnight at room temperature. The mixture was filtered and the filtrate evaporated. The residue was filtered through a short pad of silica eluting with 10% 7M NH3/MeOH in dichloromethane. The filtrate was evaporated to give the title compound as an orange oil (4.8 g, 99%).
Reaction SMILES: FC(F)C(N[C@H](CF)[C@H](O)C1C=CC(C2C=NC(C3(O)COC3)=CC=2)=CC=1)=O.[F:29][CH:30]([F:57])[C:31]([N:33]1[C@H:37]([CH2:38][F:39])[C@@H:36]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]#[N:54])=[N:50][CH:51]=3)=[CH:42][CH:41]=2)[O:35]C1(C)C)=[O:32]>>[C:53]([CH2:52][C:49]1[N:50]=[CH:51][C:46]([C:43]2[CH:42]=[CH:41][C:40]([C@@H:36]([OH:35])[C@H:37]([NH:33][C:31](=[O:32])[CH:30]([F:57])[F:29])[CH2:38][F:39])=[CH:45][CH:44]=2)=[CH:47][CH:48]=1)#[N:54]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CC#N)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3(O)COC3)nc2)cc1)C(F)F
Product: N#CCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1

Procedure:
The product of Step 6 of Example 8 and the product of Step 1 of Example 15 are reacted using the same procedure as step 6—Example 8 and making non-critical variations the title compound is obtained (358 mg): 1H NMR (DMSO-d6) 4.27 (2H, s), 4.47-4.32 (2H, m), 4.70-4.56 (1H, m), 4.91 (1H, s), 5.92 (1H, d), 6.23 (1H, t), 7.50 (3H, m), 7.74 (2H, d), 8.15 (1H, d), 8.84 (1H, d), 8.91 (1H, s); m/z 363.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][C@@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:9])[CH2:4]1.O[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][S:16]([C:14]1[CH:13]=[CH:12][C:11]([O:20][C@@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])=[C:10]([C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][O:1][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:4]2)=[O:9])[CH:15]=1)(=[O:17])=[O:18]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(CO)C1)C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(COc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 70 °C
Reaction time: 23 h

Procedure:
To a solution of 70 mg rac-(3-Hydroxymethyl-pyrrolidin-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C1) in 1.4 ml tetrahydrofuran were added 30 mg 4-hydroxybenzotrifluoride and 50 mg diphenyl-2-pyridylphosphine. 43 mg Di-tert-butyl azodicarboxylate was added. The mixture was stirred at 70° C. for 23 hours. The solvent was removed in vacuo. The oil was purified on silica gel (eluent: ethyl acetate) to yield a yellow gum. The gum was dissolved in ethyl acetate. The solution was washed 3 times with HCl 5N, once with water, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound as a light yellow foam. MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12](COCC[Si](C)(C)C)[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OC([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43](O)=[O:44])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:44]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CCNCC3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(cn1)[nH]c1nccc(N3CCN(C(=O)C[C@@H]4CCCN4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(piperazin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.2 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (50 mg, 0.4 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (70 mg, 0.4 mmol), and triethylamine (0.1 mL, 0.7 mmol) in methylene chloride (2.5 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-70% ethyl acetate in heptane) to afford the title compound as a white foam, which was used in the next step without any further purification (140 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.B(O)(O)[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:23][CH:22]=1>>[S:23]1[CH:22]=[C:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]1=2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1csc2ccccc12
Product: COc1ccc2c(-c3csc4ccccc34)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and thianaphthene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 373(MH+).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]=[CH:21][CH:22]=[CH2:23]>CN(C)C=O>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:23][CH2:22][CH:21]=[CH:20][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC=C
Solvent: CN(C)C=O
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Temperature: 110 °C
Yield: 4 %

Procedure:
To a 250 mL glass reaction vessel there was added a dimethylformamide (10 mLs) solution of N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol (2.63 g; 10 mmols). The vessel was sealed and 1,3-butadiene (40 mmols) was introduced into the system. The reaction mixture was then heated to 110° C. and the pressure was increased from atmospheric up to approximately 50 psig. The reaction was maintained at these conditions for approximately 48 hours. The reaction vessel was then cooled to room temperature. After cooling, the reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil crystallized with ethanol:water (60:40) to give 0.11 g of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one (49% yield based on N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol starting reactant).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[Br:47][CH2:48][C:49](Cl)=[O:50]>ClCCl>[Br:47][CH2:48][C:49]([NH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])=[O:50]
Reactant: O=C(Cl)CBr
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C
Yield: 87.3 %

Procedure:
285 mg (0.55 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 25 mL of dichloromethane. 175 μL (132 mg, 1.02 mmol) of di-iso-propylethylamine was added and the solution cooled to 0° C. 110 μL (208 mg, 1.32 mmol) of bromoacetyl chloride was added in two portions within 2 h while stirring at 0° C. Upon complete addition the mixture was stirred for 19 h, allowing to warm to ambient temperature. The resulting solution was evaporated and the residue directly purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes to afford 306 mg (0.48 mmol, 87%) of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a tan solid. MS: m/z 637.9+640.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH2:4][CH:5]([OH:18])[C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:18][CH:5]1[C:6]2([CH2:7][CH2:8][CH2:9]2)[O:10][C:11]2[C:3](=[C:2]([CH3:1])[C:14]([OH:15])=[C:13]([CH3:16])[C:12]=2[CH3:17])[CH2:4]1
Reactant: Cc1c(C)c2c(c(C)c1O)CC(O)C1(CCC1)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1Cc2c(C)c(O)c(C)c(C)c2OC12CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyldimethylsilyl derivative of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3,6-diol (30 mg), prepared as described in Example 22, in 1 mL of THF was added to NaH (8 mg) suspended in THF (1.5 mL). The resulting mixture was stirred at room temperature for 10 min and methyl iodide (34 mg) was added. The reaction was stirred at room temperature for 10 h and quenched onto 30 g of ice. It was extracted with hexane/EtOAc (2:1, 3×30 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford the 6-tert-butyldimethylsilyl derivative of 3-methoxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol which was used directly for the next reaction.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1B(O)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].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[F:12]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1
Yield: 86 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 5-fluoro-6-(2-fluoro-5-methoxyphenyl)picolinic acid in 86% yield. LC/MS=266.1 (M+H), Rt=0.79 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[Br:28][C:29]1[C:30]([F:36])=[N:31][C:32](I)=[CH:33][CH:34]=1.CN(C)C=O.[F-].[Cs+]>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.[Cu]I>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)=[N:31][C:30]=1[F:36]
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Reactant: Fc1nc(I)ccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To an argon protected mixture of 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine (239 mg, 0.489 mmol) and 3-bromo-2-fluoro-6-iodopyridine (162.3 mg, 0.538 mmol) in N,N-Dimethylformamide (5 mL, 60 mmol) was added Cesium fluoride (148 mg, 0.98 mmol). Tetrakis(triphenylphosphine)palladium(0) (56.482 mg, 0.048878 mmol) and Copper(I) iodide (18.618 mg, 0.097757 mmol) were then added and the resulting mixture was stirred at 40° C. for 2 hours. The mixture was cooled to room temperature, filtered through Celite®. The filter cake was washed with EtOAc. The organic layer was washed with brine, dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as a light yellow oil, which solidified upon standing (208.1 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:37]NS(C1C=CC=CC=1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH:8]([F:37])[CH2:7][CH2:6][C:5]2=1
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
6,7-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 1c) (420 mg, 1.02 mmol) dissolved in anhydrous THF (10 mL) and cooled to −78° C. was mixed with LiHMDS (1.13 mL, 1.1 mmol, 1M solution in THF). The reaction mixture was slowly warmed to 0° C., stirred for an additional 30 min. at 0° C., then cooled to −78° C. and N-fluoro benzene sulfonamide (0.31 g, 1.3 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 15 min., quenched with saturated NH4Cl and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, the solvent was removed under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (7:93) as eluant] to obtain the title compound (160 mg, 37%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.53 (s, 1H), 8.082 (d, J=8.0 Hz, 2H), 7.69 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 5.26-5.13 (m, 1H), 3.14-3.11 (m, 1H), 3.01-2.95 (m, 1H), 2.62-2.55 (m, 1H), 2.42 (s, 3H), 2.38-2.41 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:3]=1[O:4][C:5]1[C:6]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:9][C:10]=1[CH3:11].[Se](=O)=[O:38]>O1CCOCC1>[Cl:1][C:2]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:3]=1[O:4][C:5]1[C:6]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])=[N:7][C:8]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[N:9][C:10]=1[CH:11]=[O:38]
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 51.6 %

Procedure:
1 g of the compound obtained in Example 36 and 2.1 g of selenium dioxide in 40 ml of dioxan were stirred in an autoclave at 170° C. for 7 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was dried, the solvent was evaporated and the residue was purified over silica gel with ethyl acetate/hexane. 0.53 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-yl-pyrimidin-4-ylamide, m.p. 194° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:24]C)[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Product: CCOCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 83.5 %

Procedure:
6-Amino-9-benzyl-2-(2-ethoxyethoxy)-8-methoxypurine (110 mg, 0.32 mmol) in concentrated hydrochloric acid (20 ml) was stirred at room temperature for 12 hours. The reaction mixture was evaporated in vacuo to dryness and then 28% aqueous ammonia was added thereto. The resulting crystals were filtered to give the subject compound (88 mg, yield 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:8]([CH:17]=1)[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([O-])=O.C(OC(=O)C(OC1C=CC=CC=1OC1C=CC(N)=CC=1)(C)C)(C)(C)C>>[O:18]([C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][C:8]=1[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(COC2CCCCO2)c1
Agent: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc(N)cc1
Product: Nc1ccc(Oc2ccccc2)c(COC2CCCCO2)c1

Procedure:
Compound 394D was prepared from 394C in quantitative yield by a route analogous to that used for the preparation of compound 388C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc(C(N)=O)cc1
Reaction time: 4 h

Procedure:
Pd/C (11 mg, 0.11 mmol) was added to a solution of 4-(2-azidoethyl)benzamide (200 mg, 1.05 mmol) in EtOH (4 mL). A hydrogen balloon was placed over the reaction and it stirred for about four hours. The crude reaction was filtered through a pad of celite and concentrated to give 4-(2-aminoethyl)benzamide which was used without further purification.