Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1[CH:4]=[C:5]([C:14](C)(C)C(O)=O)[CH:6]=CC=1NS(C)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:49])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38](OC)[CH:37]=2)([CH3:35])[CH3:34])C=CC=1C>>[C:5]([C:22]1[CH:21]=[CH:20][C:29]([CH2:30][NH:31][C:32](=[O:49])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])=[CH:38][CH:37]=2)([CH3:35])[CH3:34])=[CH:28][CH:23]=1)([CH3:14])([CH3:6])[CH3:4]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1NS(C)(=O)=O
Reactant: COc1cc(C(C)(C)C(=O)NCCCc2ccc(C)c(C)c2)ccc1NS(C)(=O)=O
Product: CC(C)(C)c1ccc(CNC(=O)C(C)(C)c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
Through similar procedure to that in Example 1-5 excepting using 2-(3-methoxy-4-(methylsulfonylamino)phenyl)-2-methylpropionic acid (8-12), N-[3-(3,4-Dimethylphenyl)propyl]-2-[3-methoxy-4-(methylsulfonylamino)phenyl]-2-methylpropionamide (9-6, CHK-600) having following physicochemical properties was synthesized:
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([CH:16]([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:35]=2[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([NH:43][C:2]3[N:24]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([CH:16]([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:42][C:35]=2[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.182 g, 506 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.199 g, 759 mmol) in a manner analogous to Example 311a and 311b to give product: 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.10 (br m, 1H) 7.05 (m, 2H), 6.35 (br m, 1H), 4.43 (m, 2H), 3.40 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H). MS=586 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-:32].[Na+].Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:30]([NH2:31])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCCCC3)s2)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCCCC3)s2)c1
Temperature: 100 °C
Yield: 8.7 %

Procedure:
A mixture of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile (45 mg, 0.10 mmol) and NaOH (1M in MeOH, 0.5 ml, 0.50 mmol) was heated at 100° C. in the microwave for 16 hrs. The mixture was brought to pH=3 by addition of HCl (1.0 N in H2O) and then partitioned between EtOAc (5 mL) and brine (5 mL). The organic layer was separated, dried (Na2SO4), filtered and the volatiles were removed under reduced pressure. The residue was purified by HPLC (gradient elution 40% to 100% CH3CN in H2O/0.1% TFA, 20 mins, 20 ml/min) to give the title compound (4.0 mg, 8.67 μmol, 8.5% yield) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:46])([CH2:43][CH2:44][CH3:45])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:46])([CH3:38])[CH2:43][CH2:44][CH3:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 54.9 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 2.16 g (14.5 mmol) of 2,2-dimethylpentanoyl chloride, to provide 1.31 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:10][CH:11]=1)=[O:6]
Reactant: COCNC(=O)C1CSC(c2ccccc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: COCNC(=O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stirring continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1h. Yield: 27.3%. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13][C:14](=[O:23])[NH:15][CH:16]1C[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:15]1[CH2:16][CH2:17][CH2:18][N:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:20][CH2:21]1)=[O:23])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Reactant: Brc1cccc(Br)n1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1

Procedure:
The preparation is carried out analogously starting from 1.02 g (4.31 mmol) of 2,6-dibromopyridine and 856 mg (4.27 mmol) of azepan-4-ylcarbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[I-:10].[Na+]>CC(C)=O>[I:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CI
Yield: 77.8 %

Procedure:
A mixture of t-butyl chloroacetate (20 g) and sodium iodide (25 g) is stirred in acetone (200 ml) for twenty hours. The acetone is removed by distillation under reduced pressure. The residue is partitioned between diethyl ether (100 ml) and water (50 ml). The ether layer is washed with water, 5% sodium thiosulfate solution, and water. The organic layer is dried over sodium sulfate, and evaporated under reduced pressure. There is obtained 25 grams of t-butyl iodoacetate. NMR: 63.5, 1.38.
Reaction SMILES: C([O:8][C@H:9]1[CH2:12][C@H:11]([C:13]2[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]=2)[CH2:10]1)C1C=CC=CC=1.C1CCCCC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.[Pd]>[OH:8][C@H:9]1[CH2:10][C@H:11]([C:13]2[N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](OCc2ccccc2)C1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 2-(trans-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.47 g, 1.23 mmol), cyclohexene (0.080 g, 0.91 mmol), and 20 wt % Pd (dry basis) on carbon, Degussa type E101 NE/W (2.45 g) in ethanol (5 mL) under argon was heated to 65° C. for 6 h, cooled to RT, and filtered through Celite®. The filtrate was concentrated in vacuo and the resulting oil was purified by silica gel chromatography to give tert-butyl 2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.31 g, 1.09 mmol, 88% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:39]([CH3:41])([CH3:40])[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=3)[NH:31]2)[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]3[C:39]([CH3:40])([CH3:41])[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=4)[NH:31]3)[CH:27]=[CH:28][CH:29]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2ccc(F)cc2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
A solution of 4-fluoro-benzoic acid (119 mg, 0.85 mmol) and 1,1′-carbonyldiimidazole (179 mg, 1.1 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.68 mmol) in N,N-dimethylformamide (1.5 mL) was added and the mixture was allowed to stir at 50° C. for 3 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(4-fluoro-benzoylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (44 mg, 15%) as a white solid: LC/MS m/e calcd for C25H23FN2O3 (M+H)+: 419.47, observed: 419.1.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[O:9]>>[OH:9][CH2:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: C=O
Reactant: O=C1CCCCC1
Product: O=C1CCCCC1CO

Procedure:
By condensing cyclohexanone (2) with formaldehyde, the 2-hydroxymethylcyclohexanone (3) is obtained, wherefrom, by reaction with phenylmagnesium bromide, 1-phenyl-cis-2-hydroxymethyl-r-1-cyclohexanol (4) is prepared, the latter being subsequently oxidized with potassium permanganate into the acid (1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[I:10].[OH-].[Na+]>C(O)(=O)C.O>[Cl:8][C:5]1[CH:6]=[C:7]([I:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: ClI
Reactant: Nc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Cl)cc1I
Reaction time: 2 h
Yield: 60.1 %

Procedure:
The solution of 2-amino-5-chloropyridine (10.0 g, 77.8 mmol) potassium acetate (7.63 g, 77.8 mmol) in 100 mL of acetic acid was heated to 85° C. and ClI (12.6 g, 77.8 mmol) in 50 mL of acetic acid was added dropwise. Reaction mixture was kept 2 h at this temperature, diluted with 1 L of water, neutralized with NaOH 1N solution to pH 7 and extracted with ethyl acetate (4×75 mL). Organic fraction were combined, washed with NaHCO3, filtered through celite and evaporated. The residue was subjected to column chromatography on silica (eluent—hexane/ethyl acetate 1/1) providing 5-chloro-3-iodopyridin-2-amine as yellow solid (11.9 g, 60%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1>O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[CH:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CCCC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Solvent: O
Product: CCCC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1N

Procedure:
Prepared analogous to Example 19(a) from 12.5 gm of 5-methyl-6-[3-nitro-4-(2-methyl-valeryl-amino)-phenyl]-3-oxo-4,5-dihydro-2H-pyridazine. After mixing with water, the product was extracted with ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:6]=[C:3]([CH2:4][CH3:5])[CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)COc1ccc(C#N)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
1-Bromo-2-butanone (1.51 g, 10 mmol) was added to a solution of 4-hydroxybenzonitrile (1.19 g, 10 mmol) and caesium carbonate (3.25 g, 10 mmol), in acetone (50 ml). The reaction mixture was then heated at 60° C. for 2 hours. After cooling, it was concentrated under reduced pressure. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give crude 4-(2-oxobutoxy)benzonitrile intermediate (1.83 g) (9.6 mmol). Ethyl formate (407 mg, 5.5 mmol) was added to a solution of the crude intermediate (945 mg, 5 mmol) in ethanol (5 ml). The reaction mixture was then cooled to 0° C. and sodium ethoxide (21% wt solution in ethanol, 1.78 ml, 5.5 mmol) was added dropwise over 2 minutes at 0° C. under nitrogen. The reaction mixture was then warmed to room temperature and stirred for 18 hours, after which time 0.5N hydrochloric acid (25 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure to provide crude 4-(1-formyl-2-oxobutoxy)benzonitrile (820 mg, 3.78 mmol). This intermediate was then dissolved in acetic acid (10 ml), and then hydrazine hydrate (320 mg, 6.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, under nitrogen. It was then concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:pentane (30:70 to 40:60, by volume), to provide the title compound (118 mg, 15%) as a solid.
Reaction SMILES: [OH-:1].[Li+].C[O:4][C:5](=[O:39])[CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([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)[N:8]=1.O>O.CO>[OH:1][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:4])=[O:39])=[N:8][C:9]=1[C:13]1[CH:14]=[C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]2=[N:17][CH:18]=1
Reactant: [OH-]
Reactant: COC(=O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)n1
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3nc(CC(=O)O)ccc3O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.4 %

Procedure:
4 N aqueous lithium hydroxide (17 μl, 0.66 mmol) was added to hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester (286 mg, 0.55 mmol) in water/methanol(3:1) (5 ml) and stirred at room temperature for 3 days. Water was added and the mixture was extracted with ethyl acetate (3×), the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to give 5-hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid (174 mg, 61% yield) as an off white powder. MS: m/z 507.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([Cl:30])C(=O)C1>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1nc(Cl)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 35 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (250 mg, 0.80 mmol) was suspended in dry THF (10 mL) and 1 mol eq. of NCS (110 mg, 0.80 mmol) was added. The mixture was warmed to 35° C. and stirred in the dark overnight. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 235 mg (85% yield) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 96.4 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 1.5 g) and 1-fluoro-4-nitrobenzene (1.4 g, 10.0 mmol) in acetonitrile (100 mL) was added potassium carbonate (2.1 g, 15.2 mmol) and the mixture was stirred at reflux for 5 hours. The resulting mixture was concentrated and partitioned between ethyl acetate (3 times 30 mL) and water (100 mL). The combined ethyl acetate layers were dried over sodium sulphate, filtered and concentrated under vacuum. The crude product thus obtained was purified by column chromatography on silica gel (EtOAc: PE=1:20) to afford the title compound as a solid (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccccc1-c1nsc(Cl)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of 2-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.88 g (87.4%) of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(C)(=O)=O)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.49 mmol) in pyridine (74 mg, 0.94 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of methanesulfonyl chloride (80 mg, 0.70 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide (120 mg, 64.5%) as a white solid. MS (ESI+APCI) M+1=399.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N[C@@H]1CC[CH2:18][CH2:17][C@H:16]1[OH:21].C[Si](C)(C)N[Si](C)(C)C.[Na].IC1COC1>C(O)(C)C.CCO.[Ni](I)I>[O:21]1[CH2:16][CH:17]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: IC1COC1
Solvent: CC(C)O
Solvent: CCO
Product: CC(=O)Nc1ccc(C2COC2)cc1
Temperature: 80 °C
Yield: 950.8 %

Procedure:
(4-Acetamidophenyl)boronic acid (670 mg, 3.7 mmol), Nickel (II) iodide (35 mg, 0.11 mmol), trans-2-aminocyclohexanol (17 mg, 0.11 mmol), and Sodium hexamethyldisilazane (690 mg, 3.7 mmol) were weighed into a microwave reaction vial. A septum was placed over the top, nitrogen was purged and Isopropyl alcohol (5.7 ml, 75 mmol) was added. The vial was purged with nitrogen for 10 minutes and 3-iodooxetane (344 mg, 1.87 mmol) was added in 0.75 ml isopropyl alcohol. The septum was replaced with a microwave vial cap and the mixture was heated in a microwave reactor (microwave conditions: CEM Discovery Explorer microwave reactor; Ramp time: 10 min; 80° C. for 30 min; power: 300 W). The crude reaction mixture was diluted with 8 ml EtOH and the suspension was filtered through a pad of Solka floc®. The pad was washed with 35 ml EtOH and the filtrate was concentrated. The crude material was purified by flash chromatography (SiO2, eluting with 40-60% EtOAc/CH2Cl2) to give the desired product as an oil (200 mg).