Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].COCCOC.O>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C3CC3)c2)N=C1N
Temperature: 165 °C

Procedure:
To a microwave vessel containing 2-amino-4-(3-bromophenyl)-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one (103 mg, 0.25 mmol) and cyclopropylboronic acid pinacol ester (84 mg, 0.5 mmol) in 4 ml of 1:1:3 ratio of EtOH:water:1,2-dimethoxyethane, palladium(0) teterakis and aqueous sodium carbonate (400 μL of 2N solution) were added. The reaction mixture was heated in CEM microwave at 165° C. (40 mW power) for 8 minutes. The reaction mixture was filtered, and partitioned between DCM and water. The water layer was extracted w/DCM and the combined organic layer was dried (MgSO4) and concentrated under reduced pressure to afford crude product which was purified by reverse chromatography ((M+H)+ 372.4).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:53])=[N:48][CH:49]=[CH:50][C:51]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:47]([Cl:53])=[N:48][CH:49]=[CH:50][C:51]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccnc(Cl)c1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2,4-dichloropyridine hydrobromide and isolated as light green solid. MS (m/e): 442.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[CH2:13]([NH:16][CH:17]1[CH2:25][CH2:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH2:18]1)[CH2:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH2:13][CH2:14][CH3:15])[CH:17]2[CH2:25][CH2:24][C:20]3[N:21]=[CH:22][S:23][C:19]=3[CH2:18]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2ncsc2C1
Yield: 74 %

Procedure:
42A is prepared from 4-formyl-benzoic acid methyl ester and 1C as described for 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.IC1C=CC=CC=1N(C1C=CC=CC=1)C1C=CC=CC=1>[Cu].ClC1C=CC=CC=1Cl>[CH:19]1[CH:20]=[CH:21][C:16]([N:15]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Ic1ccccc1N(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 35 %

Procedure:
A mixture of 1-bromo-4-iodobenzene (11.30 g., 40 mmol.), diphenylamine (6.65 g., 39.3 mmol.), powdered potassium carbonate (26.6 g., 192.7 mmol.), 18-crown-6 (1.06 g., 4 mmol.), copper bronze (1.37 g., 21.6 mmol.), and 1.2-dichlorobenzene (40 ml) was kept at 190° C., cooled and filtered. The residue left on concentration of filtrate, was chromatograhped on silica gel. After elution with hexanes (1 liter), the product came out in 9:1 toluene hexanes eluates, and was isolated as a colorless solid after trituration with methanol, 4.47 g. (35% yield), m.p. 113-115° C. Mass Spec (m/z): 371 (M+iodotriphenylamine), 323 325 (M+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccncc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncc3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylisonicotinamide.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[C:24]4[CH:31]=[C:30]([CH2:32][OH:33])[NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:8][CH:7]=1.O1CCCC1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[C:24]4[CH:31]=[C:30]([CH:32]=[O:33])[NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:20][CH:21]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CO)cc23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
After adding 3 ml of chloroform and 50 mg of manganese dioxide to 18 mg of 1-(4-fluorophenyl)-3-[4-(6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea, the mixture was stirred overnight at room temperature. Tetrahydrofuran and ethyl acetate were added to the reaction system, and the mixture was filtered with celite and concentrated to dryness to obtain 16 mg of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:49][C:50]1[C:58](O)=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[N:53][NH:54]2.Cl.O1CCOCC1>O1CCCC1.CO>[NH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:21]([O:20][C:58]2[C:50]([CH3:49])=[C:51]3[C:55](=[CH:56][CH:57]=2)[NH:54][N:53]=[CH:52]3)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCCC(O)C1
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1c(OC2CCCCNC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (146 mg, 0.559 mmol), tert-butyl 3-hydroxyazepane-1-carboxylate (100 mg, 0.466 mmol) and diisopropyl azodicarboxylate (101 μl, 0.512 mmol) were added at 0° C. to a solution of the 4-methyl-1H-indazol-5-ol (69 mg, 0.466 mmol) obtained in Example 402 in tetrahydrofuran (4 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. After the aqueous layer was re-extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (2 ml) at room temperature, and 4N-hydrochloric acid-dioxane (2 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure and the resulting residue was dissolved in methanol (5 ml). The resulting solution was adjusted to pH 10 by dropwise addition of a 2M-aqueous sodium hydroxide solution. The solution adjusted was concentrated under reduced pressure and the resulting residue was re-dissolved in methanol (5 ml). Silica gel (1 g) was added thereto and the resulting mixture was concentrated under reduced pressure and then dried. The resulting solid was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 5-(azepan-3-yloxy)-4-methyl-1H-indazole (45.1 mg, 39%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:30](=[O:31])[N:14]2[C:15]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:16][C:17](=[O:19])[S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.[N+](C)([O-])=O>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:30](=[O:31])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[CH:16][C:17](=[O:19])[S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=CC(=O)S[C@H]12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=CC(=O)S[C@H]12
Reaction time: 0.42 h
Yield: 80.2 %

Procedure:
To a solution of benzyl 7β-(2-phenoxyacetamido)-2-oxo-3-cephem-4-carboxylate (369 mg) in methylene chloride (15 ml) were added successively anisole (1.37 ml) and a solution of aluminum chloride (560 mg) in nitromethane (5 ml) under ice-cooling. The mixture was stirred for 25 minutes at the same temperature and poured into a mixture of methylene chloride and dil. hydrochloric acid. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. After addition of diisopropyl ether to the residue, the precipitates were collected by filtration and then washed with a small amount of diethyl ether to give 7β-(2-phenoxyacetamido)-2-oxo-3-cephem-4-carboxylic acid (235 mg). mp 158° to 160° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:11]([N:12]([CH3:17])[CH:13]=[N:14]3)=[C:10](OC)[N:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22].Cl.[OH-].[Na+].CN(C=O)C.S(Cl)([Cl:33])=O>O.C(OCC)(=O)C>[Cl:33][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:21][CH3:22])[C:4]=2[F:20])[N:16]=[C:15]2[C:11]=1[N:12]([CH3:17])[CH:13]=[N:14]2
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)ccc(-c2nc(OC)c3c(ncn3C)n2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(Cl)c3c(ncn3C)n2)c1F
Temperature: 0 °C
Yield: 49.3 %

Procedure:
2-(4-Chloro-2-fluoro-3-methoxyphenyl)-6-methoxy-7-methyl-7H-purine (1.0 g, 3.1 mmol) was combined with 10 mL 6M HCl and heated at reflux for 2 h. After cooling, the mixture was diluted with 15 mL water and the pH was adjusted to 2 by addition of 2M aqueous sodium hydroxide. The precipitated material was collected by filtration, washed with water and dried under vacuum at 80° C. A 500 mg sample of the crude intermediate was slurried in chloroform (10 mL), treated with DMF (0.62 mL, 580 mg, 8.0 mmol) and then with thionyl chloride (0.58 mL, 950 mg, 8.0 mmol). The mixture was heated at reflux for 3 h, cooled and poured into 20 mL of ice-water. The pH was adjusted to 10 by addition of 1M sodium hydroxide. The precipitated product was taken up in ethyl acetate, washed twice with water, once with brine, dried and evaporated to give the title compound (500 mg, 49% yield over two steps): mp 184-186° C.: 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 7.8 (dd, 1H), 7.46 (dd, 1H), 4.11 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:9]([NH:11][NH2:12])=[O:10])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6]>O>[NH2:1][C@H:2]([C:9]([NH:11][NH2:12])=[O:10])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6]
Reactant: NNC(=O)CC[C@@H](N)C(=O)NN
Solvent: O
Product: NNC(=O)CC[C@H](N)C(=O)NN

Procedure:
The L-Glutamic dihydrazide was prepared by the same procedure as in the synthesis of D-glutamic dihydrazide. Mp 149°-150° (dec); [α]D27 26.0 (c0.5, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1>CCOC(C)=O.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
4-Chlorobenzylideneacetone (1 g, 5.5 mmol) was dissolved in EtOAc (10 mL) then platinum(IV) oxide (catalytic amount) was added. The mixture was purged with N2 (g) then H2 (g) then stirred under H2 atmosphere for 2 hours. The mixture was purged with N2 (g) then filtered to remove the catalyst. The crude material was purified on silica gel to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([O:8][CH2:20][O:21][CH3:22])=[N:6][CH:7]=1
Reactant: COCBr
Reactant: CN(C)C=Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1ncc(F)c(N=CN(C)C)n1
Yield: 18.5 %

Procedure:
N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and bromomethyl methyl ether (75 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was placed directly onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-80% gradient) to isolate 23 mg, 0.1 mmol (19%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 3.53 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H); HPLC-MS (ESI) m/z 229 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].C1C=C(C(C2C=CC(O)=CC=2)C2C=CC([OH:29])=CC=2)C(C(O)=O)=CC=1>O>[OH:29][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1ccc(CCl)cc1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccc(CO)cc1

Procedure:
30 g (0.15 mol) of 4-chloromethyl-hydrocinnamic acid (J. Org, Chem. 26, 148 (1961) in 200 ml of water were neutralized with a 10% sodium hydroxide solution against phenol phthaline. 10% of NaOH (on the whole about 60 ml) were added dropwise, while stirring at reflux temperature, to the solution obtained in the same measure as it was consumed. When the reaction was finished, the mixture was saturated with sodium chloride, acidified with concentrated hydrochloric acid, the product precipitated was suction-filtered and washed with water. Melting point: 124° - 126° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1cccc(Cl)n1
Solvent: O
Product: Cc1cccc(NN)n1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 2-chloro-6-methylpyridine (50.6 g, 397 mmol) and hydrazine hydrate (80 mL, 1.65 mol) was heated under reflux for 20 hours. The reaction solution was allowed to cool to room temperature, and excess hydrazine hydrate was evaporated under reduced pressure, and the residue was poured into water. The solution was made basic by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was chilled to crystallize, and the resulting crystals were washed with petroleum ether to give the title compound (31.0 g, 63% yield).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]#[C:8][C:9]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:29]1([S:26]([N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]2[CH:17]=[CH:16][C:15]([C:9]([OH:14])([C:10]([F:11])([F:12])[F:13])[C:8]#[C:7][C:6]([OH:35])=[O:5])=[CH:20][CH:19]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)CN(c1ccc(C(O)(C#CC(=O)OC(C)(C)C)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(c1ccc(C(O)(C#CC(=O)O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.56 g (1.1 mmol) of 4-[4-(benzenesulfonyl-isobutyl-amino)-phenyl]-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid tert-butyl ester (Example 71) in 15 mL of CH2Cl2 was added 0.3 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 24 h. After this time the solvent was evaporated, and the residue was purified by chromatography (silica, hexanes:EtOAc, 1:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH:18]=[CH:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)#[CH:26].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.CO.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH:18]=[CH:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:13]3)[N:9]=[C:10]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:3]=12
Reactant: CN(C)CC=CC(=O)N1CC[C@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: C#Cc1cccc(OC)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(C#Cc2nn([C@H]3CCN(C(=O)C=CCN(C)C)C3)c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
PdCl2(dppf)CH2Cl2 (1.3 mg) was added to a mixture of (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one (8.0 mg) obtained in Step 1, 1-ethynyl-3-methoxybenzene (4.0 mg), copper (I) iodide (0.6 mg), and triethylamine (8.6 μl) in THF (1.0 ml). After nitrogen purging, the resulting mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and methanol. The resulting diluted solution was treated with basic silica gel, and then concentrated. The resulting residue was purified by reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.4 mg). Table 2 shows the physical properties thereof.
Reaction SMILES: BrCCBr.[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[CH2:8]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:31]=2Cl)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.[Zn].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:31]=2[CH2:8][C:7]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:6]=2[Cl:5])=[O:29])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Reactant: Fc1ccc(Cl)c(CBr)c1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: BrCCBr
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3cc(F)ccc3Cl)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
To a suspension of zinc (176 mg, 2.69 mmol) in dry THF (1 ml) in a dry flask under argon was added 1,2-dibromoethane (5.79 μl, 67.2 μmol). The mixture was heated three times to reflux with a heat-gun. After 5 min the flask was placed in an ice bath and a solution of 2-chloro-5-fluoro-benzylbromide (182 μl, 1.34 mmol) in dry THF (1.5 ml) was added slowly, so that the temperature remained at 0° C. The mixture was stirred at 0° C. for 3 h. Then the cooled suspension was added dropwise to a precooled solution (0° C.) of the compound of example 16, step 1 (59.0 mg, 134 μmol), nickel acetylacetonate (3.44 mg, 13.4 μmol) and tetrabutylammonium iodide (149 mg, 402 μmol) in THF (4 ml) and NMP (2 ml). The reaction mixture was stirred at 0° C. for 3 h and then at room temperature for 48 h. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 17 mg of the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]([CH3:16])[C:6]2[C:11]([C:12]=1[C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(N(C)C)=O>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:13](=[O:15])[CH3:14])=[C:4]1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(Cl)n(C)c2ccccc12
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1c(Oc2ccccc2)n(C)c2ccccc12
Temperature: 90 °C
Yield: 75 %

Procedure:
A 203 mg portion of sodium hydride (60% oil dispersion) and 734 mg of 1-(2-chloro-1-methyl-1H-indol-3-yl)ethanone synthesized from oxyindole in accordance with the method of “European Journal of Medicinal Chemistry”, 1991, vol. 26, p. 179-188, were added in that order at room temperature to a mixed solution of 498 mg of phenol and 10 ml of dimethylacetamide and stirred at 90° C. for 2Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 703 mg of 1-(1-methyl-2-phenoxy-1H-indol-3-yl)ethanone as a colorless solid. EP: 266.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH3:13].C(O)(=O)C.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([NH:23][CH2:22][CH:19]1[CH2:21][CH2:20]1)[C@@H:8]2[CH3:13]
Reactant: COc1cccc2c1CCC(=O)C2C
Reactant: NCC1CC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc2c1CC[C@H](NCC1CC1)[C@@H]2C
Temperature: 80 °C

Procedure:
To a solution of 5-methoxy-1-methyl-2-tetralone (2.0 g) in absolute ethanol (50 ml) are added acetic acid (1.9 g), cyclopropylmethylamine (2.0 g) and 4 Å molecular sieves. The mixture is heated in a closed flask at 80° C. for one hour. The molecular sieves are filtered off and the solution is hydrogenated (PtO2) at atmospheric pressure. The catalyst is filtered off (Celite) and the volatiles are evaporated. Dilute hydrochloric acid (50 ml) is added to the solid residue. The resulting acidic solution is washed with ether, made basic 5% sodium hydroxide and extracted twice with ether. The ether extracts are combined, dried (sodium sulfate) and evaporated. The resulting crude base is eluted through an alumina column with ether-light petroleum (1:4).