Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](/[N:5]=[C:6](\OCC)/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][CH2:2][C:3]1[N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=1
Reactant: NNc1ccccc1
Reactant: CCO/C(=N\C(=O)CCl)c1cccc(F)c1
Product: Fc1cccc(-c2nc(CCl)n(-c3ccccc3)n2)c1

Procedure:
The product was obtained starting from (Z)-ethyl N-2-chloroacetyl-3-fluorobenzimidate (535 mg, 1.98 mmol) and phenylhydrazine (270 mg, 246 μL, 2.37 mmol) according to the method described in example 57, step 2 as orange solid (448 mg, 1.56 mmol, 78.8%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[CH:18]([CH3:33])[C:17]2=[O:34])[C:13]([OH:15])=O)[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[CH:18]([CH3:33])[C:17]2=[O:34])[C:13]([N:37]([CH3:38])[CH3:36])=[O:15])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2
Reactant: CNC
Reactant: CC1C(=O)N(C(CCN2CCC3(CC3)[C@H](O)C2)C(=O)O)CCN1c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(C(CCN2CCC3(CC3)[C@H](O)C2)C(=O)N(C)C)CCN1c1cccc(OC(F)(F)F)c1
Yield: 71.4 %

Procedure:
To a solution of 4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-butyric acid (example 48; 40 mg, 82 μmol) in N,N-dimethylformamide (1.5 mL) was added dimethylamine hydrochloride (10 mg, 0.12 mmol), triethylamine (33 mg, 0.33 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg, 99 μmol), then after 1 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (30 mg, 71%). Colorless oil, MS: 513.5 (M+H)+.
Reaction SMILES: C1COCC1.I[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[CH:26])([CH3:19])([CH3:18])[CH3:17]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[C:26][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a mixture of anhydrous THF and triethylamine (20 mL, 1/1) were sequentially added 1-iodo-4-nitrobenzene (2.0 g, 8.032 mmol) and copper (I) iodide (0.31 g, 1.606 mmol). The mixture was stirred at room temperature for 15 min. The flask was evacuated and re-filled with argon four times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)-palladium(II) (0.56 g, 0.803 mmol) was added into the mixture under argon protection, followed by dropwise addition of but-3-ynyl-carbamic acid tert-butyl ester (1.62 g, 9.638 mmol). The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in methylene chloride and purified by column chromatography, eluting with a mixture of ethyl acetate (0–10%) and hexanes (100–90%) to afford 2.08 g (89%) of the product 51 as an orange solid. 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.66 (t, J=6.5 Hz, 2H), 3.36–3.43 (m, 2H), 4.86 (br s, 1H), 7.53 (d, J=8.7 Hz, 2H), 8.16 (d, J=8.7 Hz, 2H). m/z (APCI)=291 [C15H18N2O4+H]+, 191 [C15H18N2O4-Boc+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[N:18]1C=CC=C[CH:19]=1.CN>C(Cl)Cl>[CH3:19][NH:18][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(O)c1
Reaction time: 1.5 h
Yield: 24 %

Procedure:
A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][N:6]=1)=[O:4].N/[C:17](=[CH:20]\[CH3:21])/[C:18]#[N:19]>CC(O)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[C:13]([C:5]#[N:6])=[C:8]([CH3:9])[NH:7][C:20]([CH3:21])=[C:17]3[C:18]#[N:19])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc(C=O)cc12
Reactant: C/C=C(\N)C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 177.3 %

Procedure:
A mixture of 5-formyl-1H-indazole-3-carboxylic acid methyl ester (92 mg, 0.45 mmol) and aminocrotononitrile (74 mg, 0.9 mmol) in HOAc (1 mL) was kept at 110° C. for 15 mins. After cooling to rt, the reaction mixture was diluted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by TLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid methyl ester (133 mg, 89%) (Cpd. No. 85, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.04 (s, 1H), 7.72 (s, 1H), 7.49 (d, 1H), 4.58 (s, 1H), 4.02 (s, 3H), 2.0 (s, 6H) ppm.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH3:15][C:16]1[C:24]2[CH2:23][CH2:22][O:21][C:20]=2[C:19]([CH:25]=[CH:26][C:27](=[O:29])[CH3:28])=[C:18]([CH3:30])[C:17]=1[CH3:31]>C1(C)C=CC=CC=1>[CH3:15][C:16]1[C:24]2[CH:23]=[CH:22][O:21][C:20]=2[C:19]([CH:25]=[CH:26][C:27](=[O:29])[CH3:28])=[C:18]([CH3:30])[C:17]=1[CH3:31]
Reactant: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1c(C)c(C)c(C)c2ccoc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.0 g) was added to a solution of 1-(4,5,6-trimethyl-2,3-dihydrobenzo[b]furan-7-yl)-but-1-en-3-one (5.0 g) in toluene (100 ml) and the mixture was stirred at room temperature for a period of 24 hours. The solvent was evaporated by distillation under reduced pressure and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 1-(4,5,6-trimethylbenzo[b]furan-7-yl)but-1-en-3-one (4.2 g; 85%) as a pale yellow solid, mp 99° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]([CH3:12])[CH:10]=[CH:9][CH:8](OCC)[O:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:18])=O>CCOCC>[C:1]([O:4][CH2:5][CH:6]1[CH:11]([CH3:12])[CH:10]([Cl:18])[CH:9]=[CH:8][O:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC1C=CC(C)C(COC(C)=O)O1
Solvent: CCOCC
Product: CC(=O)OCC1OC=CC(Cl)C1C
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
To a solution of 0.113 g. (0.53 mmol) of 3-methyl-6-ethoxy-3,6-dihydro-2H-pyran-2-methanol acetate in 2 ml. of ether at 0° was added 0.12 g. (1.0 mmol) of thionyl chloride. The mixture was stirred at 0° for 1 hour, at room temperature for 4.75 hours and concentrated to give 0.098 g. (103%) of the crude chloroenol-ether as a colorless oil (ca. 70% pure by nmr).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Cc1ccc(O)cc1N
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Yield: 58 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (743 mg, 2.26 mmol), 3-amino-4-methylphenol (446 mg, 3.62 mmol), potassium carbonate (782 mg, 5.66 mmol) and N,N-dimethylformamide (5.0 mL) was stirred using a microwave synthesizer at 180° C. for 30 min. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→75/25) to give the title compound (424 mg, 58%) as a brown powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21]([CH:34]=[O:35])=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(Br)c(F)n2)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1F
Temperature: -45 °C
Yield: 70.4 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (26, 2.90 g, 6.74 mmol) in 25.0 mL of tetrahydrofuran at −35° C. under an atmosphere of nitrogen, isopropylmagnesium chloride (3.54 mL, 2.00 M in tetrahydrofuran, 7.08 mmol) was added and the reaction was allowed to come to 0° C. over an hour. The reaction was cooled to −45° C. and N,N-dimethylformamide (1.0 mL, 13.0 mmol) was added. The reaction was allowed to warm to room temperature over 2 hours, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (27, 1.80 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[N:4][CH:3]=[N:2][CH:7]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1cncnc1
Agent: Cl
Product: O=C(Cc1cncnc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrimidin-5-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 250, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrimidin-5-yl)acetamido)propanamide. 1H-NMR (400 MHz, CDCl3): σ 9.17 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.42-7.21 (m, 7H), 7.06-6.91 (m, 5H), 6.68 (d, 1H), 4.70-4.63 (m, 3H), 4.57 (d, 1H), 3.98 (dd, 1H), 3.60-3.54 (m, 3H). MS (EI) for C28H25FN4O4. found 501.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:8])[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (7-formyl-chroman-4-yl)-methyl-carbamic acid tert-butyl ester (554 mg, 1.90 mmol, 1.0 eq), piperidine (Aldrich, 195 mg, 2.28 mmol, 1.2 eq), NaBH(OAc)3 (Aldrich, 805 mg, 3.8 mmol, 2.0 eq) and glacial HOAc (J. T. Baker, 114 mg, 1.90 mmol, 1.0 eq) in ClCH2—CH2Cl (8 mL) was stirred at RT for 4 h. The reaction was quenched with saturated Na2CO3 (50 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-5% MeOH—CH2Cl2) afforded the title compound as colorless sticky solid. MS (ESI, pos. ion) m/z: 361 (M+1).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2NN=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(-c2nnn[nH]2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)cc1
Yield: 92 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.17 g), 5-(4-t-butylphenyl)-1H-tetrazole (1.00 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1.51, yield 92%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 210–211° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>O1CCOCC1>[OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[C:9](/[CH:14]=[CH:13]/[C:12]([O:16][CH2:17][CH3:18])=[O:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1coc2cccc(O)c12
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Yield: 20.3 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzofuran (2.9 g, 20 mmoles) palladium III acetate (4.5 g, 20 mmoles), ethyl acrylate (2 g, 20 mmoles), acetic acid (50 ml) and dioxane (200 ml) was refluxed for 3 hours. The mixture was filtered and the filtrate concentrated and chromatographed to obtain 1 g of the title compound after recrystallization from toluene, m.p. 180°-182° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:23]=3)[C:19]([Cl:37])=[CH:18][N:17]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:44][O:45][CH2:46][CH2:47]OS(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[Cl:37][C:19]1[C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:23]=2)=[CH:21][C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:8][CH2:47][CH2:46][O:45][CH3:44])[CH2:10][CH2:11]2)=[N:17][CH:18]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3F)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3F)c(Cl)cn2)CC1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-3-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine trifluoroacetate (30 mg, 0.055 mmol) and sodium carbonate (23 mg, 0.22 mmol) in DMSO (0.75 ml) was added p-toluenesulfonic acid 2-methoxyethyl ester (15 mg, 0.066 mmol). The mixture was stirred at 85° C. for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was purified by reverse phase HPLC and lyophilized to give 5.0 mg of 5′-chloro-3-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 492.2 (MH+), retention time=0.57 min.; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10-1.46 (m, 6 H) 1.64-1.74 (m, 2 H) 1.86 (br. s., 2 H) 1.95-2.09 (m, 2 H) 2.09-2.26 (m, 2 H) 2.58 (br. s., 1 H) 2.88 (t, J=5.09 Hz, 2 H) 3.17 (t, J=6.26 Hz, 2 H) 3.29-3.45 (m, 5 H) 3.53 (t, J=5.09 Hz, 3 H) 4.00 (dd, J=11.35, 3.52 Hz, 2 H) 4.34-4.47 (m, 1 H) 4.54-4.68 (m, 1 H) 6.35-6.48 (m, 2 H) 7.31 (t, J=8.80 Hz, 1 H) 8.11 (s, 1 H).
Reaction SMILES: COCCOCCOC.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].[OH:21][C:22]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:34])([CH3:33])[O:27]2>[I-].[K+]>[OH:21][C:22]1[CH:31]=[C:30]([O:32][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:33])([CH3:34])[O:27]2
Reactant: CC(C)CBr
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)COc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 100 °C
Yield: 79 %

Procedure:
In 50 ml of diethylene glycol dimethylether (DIGLIM) 4.2 g (20 millimoles) of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate and 0.2 g of potassium iodide and thereafter 3.3 g (2.6 ml, 24 millimoles) of isobutyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours and worked up according to Example 19. Thus 4.1 g of the desired compound are obtained, yield 79%. Mp.: 77°-79° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(NCC)C>CN(C)C=O>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminophenethyl alcohol (25 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (30 g) and ethyl bromoacetate (24 ml), and the mixture was stirred for 16 hours at room temperature. Diethylamine (38 ml) was added to the reaction mixture, and the resulting mixture was stirred for 1 hour. The insoluble material was filtered off and the filtrate was concentrated in vacuo. To the residue was added diethyl ether, and the resulting insoluble material was filtered off. The filtrate was washed with 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine subsequently, and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl N-[4-(2-hydroxyethyl)phenyl]aminoacetate (35.5 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:33][CH2:32]2)[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH2:37]([CH:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][CH2:28][N:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:18])[CH2:32][CH2:33]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
The compound obtained in Example 65 (4.89 g, 7.85 mmol) was dissolved in acetic acid (5 ml). To the solution was added 30% solution of hydrogen bromide in acetic acid (15 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added diethylether (60 ml), and supernatant solution was removed by decantation. To the residure was added diethylether (60 ml), and supernatant solution was removed by decantation. These procedure was repeated further three times. To the residue was added aqueous solution of 1N-sodium hydroxide (50 ml) and the mixture was extracted with dichloromethane (80 ml, 30 ml×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (alumina 200 g, ethyl acetate/methanol=1/0 to 4/1 to 1/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (3.18 g, 6.51 mmol, Yield 83%) as pale brown oily substance.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14]C(OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[N:22]([CH2:6][C@@H:7]([NH2:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[N+:23]=[N-:24]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Temperature: 65 °C
Yield: 135.7 %

Procedure:
To a solution of (2S)-2-[(tert-Butoxycabonyl)amino]-2-phenylethyl methanesulfonate (ref. Org. Syn. 2008, 85, 219) (5.0 g, 15.9 mmol) in DMF (40 mL) was added solid sodium azide (2.2 g, 33 mmol). The reaction was heated to 65° C. for 48 h. The reaction was cooled to room temperature and water was added to provide a white precipitate. The precipitate was filtered and dried under vacuum to afford the desired compound (3.5 g, 85%). To a solution of azide (0.75 g, 2.86 mmol) in THF (14 mL) was added HCl (as a 4M solution in dioxane, 7 mL, 28 mmol). The reaction was stirred at RT for 16 hours, then solvents were removed under reduced pressure to give the amine hydrochloride, which was used in the next step without further purification.