Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[C:23]#[N:24])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C[C@@H](P(C(C)(C)C)C(C)(C)C)[C]1[C](P(C2CCCCC2)C2CCCCC2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:35][C:34]([F:37])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([NH:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:15][O:16]4)=[CH:11][C:10]=3[C:23]#[N:24])=[CH:25][CH:26]=2)=[O:3])=[N:29][CH:30]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Fe]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Temperature: 90 °C
Reaction time: 5 h
Yield: 10.6 %

Procedure:
Methyl 7-(4-carbamoylphenoxy)-6-cyanochroman-4-carboxylate (58 mg, 0.17 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.021 mL, 0.17 mmol), cesium carbonate (75 mg, 0.23 mmol), (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (4.6 mg, 0.0083 mmol) and palladium(II) acetate (1.9 mg, 0.0083 mmol) were diluted with DME (1 mL). The reaction was heated to 90° C. and stirred for 5 hours. The reaction was loaded directly onto a biotage 25 cartridge (silica gel), eluting with 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes to afford methyl 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (9 mg, 11% yield) as a white solid.
Reaction SMILES: [ClH:1].Cl.[N:3]1[N:4]=[C:5]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([O:22][CH2:23][C:24]4([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[CH2:31](N(CC)CC)C.C=O.O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CN(C=O)C>[ClH:1].[ClH:1].[N:3]1[N:4]=[C:5]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([O:22][CH2:23][C:24]4([F:30])[CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: FC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCNCC1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(F)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
To a suspension of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinoline dihydrochloride (0.050 g, 0.111 mmol) and triethylamine (0.0619 mL, 0.444 mmol) in 0.6 mL DCE and 0.3 mL DMF was added 37% formaldehyde in water (0.0413 mL, 0.555 mmol). After stirring at ambient temperature for 15 minutes, Na(OAc)3BH (0.0471 g, 0.222 mmol) was added, and the reaction mixture was stirred at ambient temperature for 18 hours. Another 10 equivalents of 37% formaldehyde was added, followed by 10 equivalents of Na(OAc)3BH. The reaction mixture was stirred another 6 hours, and saturated NaHCO3 was added. The mixture was extracted with dichloromethane, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (1 mm plate, 6:1 dichloromethane: 6% NH4OH in methanol). The resulting residue was dissolved in minimal dichloromethane, and this solution was added to a vigorously stirring solution of 1.5 mL 2M HCl/ether in 15 mL ether, causing precipitation. The solids were isolated by filtration through a medium glass fritted funnel by pushing the solvent through the frit with nitrogen pressure, rinsed with ether, dried under nitrogen pressure, and dried in vacuo to give the title compound (0.015 g, 0.0323 mmol, 29.1% yield) as a white powder. MS APCI (+) m/z 392 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=1.[OH-].[Na+]>O>[CH3:24][C:23]1[C:18]([CH2:17][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: Cc1cnc(CCl)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c(C)c1

Procedure:
6.54 g of 5-(trifluoromethyl)-2-benzimidazolethiol are suspended in 400 ml of alcohol and treated with 5.76 g of 2-chloromethyl-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 800 ml of methylene choride. The solution is washed firstly with 200 ml of 1.5N sodium hydroxide solution and then 3×with 250 ml of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 110 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[(3,5-dimethyl-2 -pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 137°-138°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[N+:9]([CH3:12])([O-])=[O:10].[O-]CC.[Na+].[Na]>C(O)C.CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([CH:12]=[N:9][OH:10])=[O:8])[O:4][N:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C=O)on1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(C(=O)C=NO)on1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
In 50 ml of ethanol were dissolved 5.5 g of 3-methylisoxazole-5-carbaldehyde and 3.3 g of nitromethane. To the solution was added dropwise a solution of sodium ethoxide in ethanol, which had been prepared from 1.5 g of sodium and 30 ml of ethanol, while stirring at room temperature. After dropping the resultant was stirred for a further 3 hrs. at room temperature and then ether was added thereto to separate the sodium salt. This was dissolved in water, which was followed by acidification with hydrochloric acid. The resulting precipitate was filtered off and recrystallized from chloroform to obtain 5.4 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C. Yield, 70%; Elemental Analysis (C6H6N2O3):
Reaction SMILES: [BH4-].[Na+].[ClH:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[OH:13].C1(N=C=NC2CCCCC2)CCCCC1>[OH-].[Na+].CO.C(OCC)(=O)C>[Cl:11][C:9]1[CH:10]=[CH:5][C:6]([OH:13])=[C:7]([Cl:3])[C:8]=1[Cl:12]
Reactant: Cl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
Ethyl 5'-(4-formyl-3,5-dimethoxyphenoxy)valerate (13.2 g, 42.5 mmol) was dissolved in 1 n NaOH-MeOH (1:1) (100 mL) and after 10 minutes of stirring sodium borohydride (2.2 g, 60 mmol) was added portionwise over 45 minutes. After stirring two additional hours at 25° C., the solutions was chilled to 4° C., acidified with 1 N HCl to pH 5, and extracted with ethyl acetate (4×25 mL). The combined organic phases were washed with saturated aqueous NaCl (2×25 mL) and dried over MgSO4. 2,4,5-trichlorophenol (6.9 g, 35 mmol) and N,N'-dicyclohexylcarbodiimide (7.2 g, 35 mmol) were added to the ethyl acetate solution. The mixture was stirred overnight at 25° C. and then N,N-dicyclohexylurea was removed by filtration. The filtrate was washed with carbonate buffer, pH 9.5 (3.50 mL), and with saturated aqueous NaCl (2.25 mL), dried (MgSO4) and rotary evaporated. The residue was recrystallized from ethyl acetate with pentane added at 25° C. and was further chilled to -5° C. to provide a slightly orange solid (11.6 g, 25 mmol, 59% yield with respect to formyl derivative or 72% yield to trichlorophenol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.C1C=CC=CC=1.N12CCCN=C1CCCCC2.[C:33]([OH:36])(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[C:33]([O:36][CH2:14][C:5]1[C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([Br:1])[CH:3]=2)[O:8][C:7](=[O:13])[CH:6]=1)(=[O:35])[CH3:34]
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Reactant: CC(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCc1cc(=O)oc2cc(O)c(Br)cc12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of 67.1 mg (0.232 mmol) of compound 11, dry benzene (2 mL), 175 mL (0.927 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 mL (0.70 mmol) of acetic acid was refluxed for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (10 mL), quenched with 1N HCl (1 mL) and separated. The organic layer was dried over MgSO4 and evaporated to yield the crude product. Purification by column chromatography (10 g of SiO2, 4.7% methanol-chloroform) gave 43.1 mg (0.138 mmol, 59.4% yield) of compound 5 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.56 (1H, s), 6.80 (1H, s), 6.21 (1H, s), 5.14 (2H, s), 2.11 (3H, s); MS (ES, negative) 311.0 and 313.1; UV (KMOPS, pH 7.2) λmax (ε) 370 nm (15,000 M−1cm−1).
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Reactant: CN(C)C(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C=C2C(=C(C3=CCN(CC(=O)N(C)C)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 70 °C

Procedure:
To a suspension of Example 48 (100 mg, 0.284 mmol) in N,N-dimethylformamide (4 mL) was added triethylamine (0.237 mL, 1.703 mmol) and 2-chloro-N,N-dimethylacetamide (41.4 mg, 0.341 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 10-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.57-2.62 (m, 2H), 2.79 (t, J=5.04 Hz, 2H), 2.84 (s, 3H), 2.89 (s, 3H), 3.03 (s, 3H), 3.30-3.37 (m, 4H), 4.07 (s, 2H), 5.85 (s, 1H), 7.26-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.62-7.66 (m, 1H), 8.24 (d, J=5.19 Hz, 1H), 11.62 (s, 1H). MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1>C(OCC)(=O)C.[Pt]>[F:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:2]([F:1])=[CH:7][C:6]=1[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 95.5 %

Procedure:
A solution of 2.63 g (9.3 mmol) of 1,4-difluoro-2-(3-fluoro-benzyloxy)-5-nitro-benzene in 25 ml of ethyl acetate is hydrogenated with Pt/C (5%) as the catalyst under normal pressure during 3 hours. For the working-up, the catalyst was filtered over a Dicalit layer and the solution evaporated under reduced pressure. There are obtained 2.25 g (95% of theory) of 2,5-difluoro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid; MS: m/e=253 (M)+. The crude product is engaged in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:54]=[C:55]([F:57])[CH:56]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=5)=[C:22]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:21]=4)[CH:18]=3)[N:13]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:12]=2)=[N:7]1>[N+](C1C=C(C=CC=1)CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)([O-])=O.[OH-].[Pd+2].[OH-]>[F:57][C:55]1[CH:54]=[C:4]([CH:3]=[C:2]([F:1])[CH:56]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[C:22]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH:21]=4)[CH:18]=3)[N:13]([S:44]([C:47]3[CH:48]=[CH:49][C:50]([CH3:51])=[CH:52][CH:53]=3)(=[O:46])=[O:45])[CH:12]=2)=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 79.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.307 mmol) was reduced with palladium hydroxide (250 mg) in ethyl acetate/ethanol 10/10 mL to afford 200 mg (80% yield) of the titled compound. MS: m/z=817.7 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:48])[C:6]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:45][CH2:44][CH2:43][C@@H:19]4[S:20](=[O:42])(=[O:41])[C:21]([CH3:40])([CH3:39])[C:22]([N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:23][C@:18]4([CH2:46][F:47])[C:16]=3[CH:17]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:24][C:22]1[C:21]([CH3:40])([CH3:39])[S:20](=[O:41])(=[O:42])[C@H:19]2[CH2:43][CH2:44][O:45][C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[C:6]4[C:5]([CH3:48])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=4)=[CH:17][C:16]=3[C@@:18]2([CH2:46][F:47])[N:23]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(CF)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@H]1CCO2
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(CF)N=C(N)C(C)(C)S(=O)(=O)[C@H]1CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a 50-mL round-bottomed flask was added tert-butyl N-[(4aS,11bS)-10-[(5-cyano-3-methyl-pyridine-2-carbonyl)amino]-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (129 mg, 0.188 mmol), DCM (3 mL), and TFA (2 mL). The reaction mixture stirred at RT for 30 min. The solvent was removed under vacuum. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (3 mL) (3 times). The organic extract was dried over Na2SO4. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 2% 2M NH3.MeOH in DCM, to provide N-((4aS,11bS)-2-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-cyano-3-methylpicolinamide (62 mg, 0.128 mmol, 67.9% yield) as an off-white solid. MS m/z=486.0 (M+H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.5 Hz), 7.89 (1H, d, J=8.7 Hz), 7.82 (1H, s), 7.40 (1H, s), 7.06, (1H, d, J=6.6 Hz), 6.72 (1H, d, J=5.5 Hz), 4.74–4.65 (2H, m), 4.31–3.68 (5H, m), 3.60–3.55(2H, m), 2.68 (3H, s), 2.54–2.46 (2H, m), 1.95–1.87 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 478. found 478.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[H][H]>CCO.C(OCC)(=O)C.[Pd]>[F:24][C:22]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([OH:8])[CH:23]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Yield: 101.3 %

Procedure:
A solution of tert-butyl 2-(benzyloxy)-4-fluorobenzylcarbamate (Example 14; 9 mmol) in EtOH (80 ml) and ethyl acetate (240 ml) was treated with 1 atm of hydrogen at 25° C. over 10% Pd/C (0.4 gr) for 24 hours. The catalyst was removed by filtration through celite, washed with EtOH and the filtrate was concentrated to afford the title compound (2.2 g) as a yellow solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([C:27]([F:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:22][C:21]=2[CH2:37][CH3:38])=[O:18])=[CH:15][CH:14]=1.O.NN>C(O)C.O>[NH2:3][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([C:27]([F:36])([C:28]([F:29])([F:30])[F:31])[C:32]([F:33])([F:34])[F:35])=[CH:22][C:21]=2[CH2:37][CH3:38])=[O:18])=[CH:39][CH:40]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)cc1
Temperature: 60 °C

Procedure:
4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)-6-methylphenyl]benzamide (0.80 g) was dissolved in ethanol (20 ml). To the solution, hydrazine monohydrate (0.28 g) was added and the mixture was stirred under heating at 60° C. for 4 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl] benzamide as a crude product (0.63 g). Without further purification, the crude product was used for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=[N:15]O)=[C:12]([CH3:17])[N:11]=[C:10]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:9]=23)[CH:5]=[N:6][CH:7]=1.C(OC(=O)C)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([CH3:17])[N:11]=[C:10]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: CCn1ncc2c(-c3cncc(Br)c3)c(C=NO)c(C)nc21
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCn1ncc2c(-c3cncc(Br)c3)c(C#N)c(C)nc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (34 mg) and acetic anhydride (1 ml) was stirred at 90° C. for 2 hours and 150° C. for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2). The crystalline residue was recrystallized from EtOAc and n-hexane to give 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (15.5 mg) as a colorless crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=[C:20]2[CH3:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: COc1ccc(-n2c(C)nc3cnccc32)cc1
Yield: 70.2 %

Procedure:
Method B applied to 4-chloro-3-nitropyridine (79 mg, 0.5 mmol) and N-(4-methoxyphenyl)acetamide (99 mg, 0.6 mmol) afforded the title compound as viscous oil (84 mg, 70%). 1H NMR (DMSO) δ 2.55 (s, 3H), 3.88 (s, 3H), 7.21 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.69 (d, J=5.4Hz, 1H), 8.57 (d, J=5.4Hz, 1H), 9.44 (s, 1H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:40]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][CH2:40][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Solid NaBH(OAc)3 (1.4 g, 6.8 mmol) was added to a DCM solution (10 mL) of tert-butyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (1.3 g, 3.4 mmol) and 4-bromoaniline (882 mg, 5.1 mmol), and the resulting mixture was stirred at room temperature. After 40 h the resulting mixture diluted with DCM and saturated aqueous Na2CO3 and stirred vigorously. After 5 min, the layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:34][O:35][C:36]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:37]=1[CH2:38][N:39]1[C:42](=[O:43])[C@@H:41]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:40]1[CH:55]=O>C1COCC1>[CH3:34][O:35][C:36]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:37]=1[CH2:38][N:39]1[C:42](=[O:43])[C@@H:41]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:40]1/[CH:55]=[CH:2]/[O:3][CH3:4]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C/[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (10.34 g, 30.2 mmol) in THF (100 mL) at −78° C. was added KHMDS (in toluene) (66.3 ml, 33.1 mmol) slowly. After stirring for 30 min, the above prepared ylide soln was added to a soln of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-formyl-4-oxoazetidin-3-yl)carbamate (3 g, 7.53 mmol) in THF (38 ml) at −78° C. After 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq, 60 mL), and it was stirred overnight. The mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-60%) to afford the title compound (1.6 g, 49%) along with the trans-isomer (0.8 g, 25%). LCMS: Rt=0.91 min, m/z=427.0 (M+1). Method 2m_acidic.