Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:19](O)[CH3:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:19][CH2:20][Cl:24])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(Cl)nc2)C(C)O)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(CCCl)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.8 grams (0.022 mole) of 2-{[(6-chloro(3-pyridyl)methyl][(4-methoxyphenyl)methyl]amino}ethan-1-ol in 200 mL of chloroform was stirred and a solution of 2.9 grams (0.024 mole) of thionyl chloride in 50 mL of chloroform was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature during one hour, and then it was warmed to reflux where it stirred for 2.5 hours. After this time the reaction mixture was cooled to room temperature and was slowly poured into a solution of 100 mL of aqueous 5% sodium carbonate. The organic layer was separated and dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using 2% diethyl ether in methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 6.4 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1)=[C:8]2[CH3:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-yloxy]-acetic acid methyl ester (0.11 g), methanol (5.0 mL), water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 3 days. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid, 0.08 g.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](O)CC2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cn3)CC2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of 200 mg (0.79 mmol) of trans-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone (Intermediate 4) in 1 ml of DMA, 42 mg (0.96 mmol) of sodium hydride was added at room temperature and stirred for 30 min. To the mixture, 220 mg (1.59 mmol) of 6-chloronicotinonitrile (commercially available) was added and stirred at 100° C. for 24 h. The mixture was poured into saturated NaHCO3 solution., extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with CH2Cl2 and methanol=from 98:2 to 95:5. The combined product fractions were evaporated to dryness to yield 33 mg (6%) of the title compound. MS (m/e): 357.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CCO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1
Reactant: NO
Reactant: CCOC(=O)CCCOc1ccc(C#N)cc1F
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 4-(4-cyano-2-fluorophenoxy)butanoate (3.50 g; 13.93 mmol; 1 eq.) was dissolved in EtOH (70 mL). Hydroxylamine (2.05 mL; 69.65 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated under vacuum affording the title compound as a white solid. (3.82 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 9.59 (br s, 1H), 7.49-7.43 (m, 2H), 7.18-7.12 (m, 1H), 5.80 (br s, 2H), 4.11-4.02 (m, 4H), 2.46-2.43 (m, 2H), 2.03-1.94 (quint., J=6.97 Hz, 2H), 1.20-1.15 (t, J=7.11 Hz, 3H). LC/MS (Method B): 285.1 (M+H)+. HPLC (Method A) Rt 2.67 min (Purity: 99.1%).
Reaction SMILES: OO.Cl[CH2:4][C:5]([C:7](Cl)(Cl)Cl)=[O:6].[CH:11]1[CH2:18][CH2:17]CCC[CH2:13][CH:12]=1.C(Cl)(Cl)Cl>O>[CH:4]12[O:6][CH:5]1[CH2:7][CH2:13][CH2:12][CH2:11][CH2:18][CH2:17]2
Reactant: C1=CCCCCCC1
Reactant: O=C(CCl)C(Cl)(Cl)Cl
Agent: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C1CCCC2OC2CC1
Yield: 83 %

Procedure:
There were added 13.68 parts of a 50% aqueous hydrogen peroxide to a refluxing mixture of 3.92 parts of tetrachloroacetone, 11.58 parts of cyclooctene and 149 parts of chloroform. Water was removed continuously as it was formed, over a period of 4 hours of heating. The removed water was then added to the reaction mixture. The organic phase was then separated from the aqueous phase. Based on VPC analysis there was obtained an 83% yield of cyclooctene oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(C=Cc3ccccc3)sc2c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ncc2cc(CCc3ccccc3)sc2c1O
Reaction time: 29 h
Yield: 53.5 %

Procedure:
A mixture of 7-hydroxy-2-styryl-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.g, 0.44 mmol) and 10% palladium on carbon (100 mg) in 20 mL of 1:1 ethyl acetate: ethyl alcohol was placed under a hydrogen atmosphere at 19 PSI on a parr shaker. At 7 hours an additional 60 mg of 10% Pd/C was added, after 24 hours an additional 75 mg of 10% Pd/C was added, and the reaction was stopped at 29 hours. The mixture was filtered through a celite pad and purified by flash chromatography, eluting the desired product from silica gel with a gradient of 20-80% ethyl acetate in hexanes to give 77 mg of desired product: MS: (+) m/z 327.9 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:48]([C:45]3[CH:44]=[CH:43][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)=[CH:47][CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 19 %

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.028 g, 0.076 mmol), EtOH (1.3 mL) and DMF (0.18 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.025 g, 0.083 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8) to give the title compound as a solid (0.009 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.62-2.70 (m, 7H), 3.29-3.35 (m, 4H), 3.55 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.67-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.44 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.66 min—623/625 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 623.2680, calculated for C31H40ClN8O2S (M+H)+: 623.2683.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[N:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]([C:12]([OH:14])=[O:13])[CH2:3]1.C([O:19][C:20](=[O:22])[CH3:21])(=O)C>>[C:2]([O:13][C:12]([N:4]1[C:5]2[CH:10]=[C:9]([CH2:11][O:19][C:20](=[O:22])[CH3:21])[N:8]=[CH:7][C:6]=2[C:2]([CH3:15])([CH3:1])[CH2:3]1)=[O:14])([CH3:6])([CH3:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(cn1)C(C)(C)CN2C(=O)O
Product: CC(=O)OCc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 125 °C
Yield: 65 %

Procedure:
3,3,6-Trimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid, 5-oxide, tert-butyl ester (0.375 g, 1.34 mmol) was dissolved in acetic anhydride (1.68 mL) and heated to 125° C. for 1 h. The reaction was cooled to ambient temperature and concentrated in vacuo. Chromatography (SiO2, gradient elution, 0-100%, EtOAc/petrol), gave the title compound (0.280 mg, 65%) as a yellow oil. MS: [M+H]+=321.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:20])[C:13]4[CH:14]=[N:15][N:16]([CH3:19])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38].CO>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[CH3:19])=[C:12]([NH:20][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)=[O:38])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cn1ncc2c(N)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c(NC(=O)c3ccccn3)cc(-c3cccc4[nH]ccc34)cc21
Reaction time: 5 h
Yield: 23.2 %

Procedure:
6-(1H-Indol-4-yl)-1-methyl-1H-indazol-4-amine (70 mg, 0.27 mmol) was dissolved in DCM (3 ml) and treated with DIPEA (0.145 ml). 2-Pyridinecarbonyl chloride hydrochloride (59.5 mg, 0.34 mmol) was added and the reaction was stirred for 5 h. MeOH (2 ml) was added and the reaction stirred overnight. The solvent was evaporated and the residue was treated with DCM/Methanol (1:1, 2 ml) then evaporated to dryness. The product was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC (Method B). Fractions containing product were combined and dried to give the title compound (23 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[C:62]([Cl:63])=[CH:61][C:57]2[O:58][CH2:59][O:60][C:56]=2[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Cl:63][C:62]1[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])=[CH:55][C:56]2[O:60][CH2:59][O:58][C:57]=2[CH:61]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cc2c(cc1Cl)OCO2
Yield: 63.9 %

Procedure:
The operation is carried out as in Stage 5 of Example 1, starting with 121 mg of L-Tryptophan in the form of the hydrochloride, 2 ml of anhydrous methylene chloride, 0.13 ml of triethylamine, 199 mg of BOP and 143 mg of the product obtained in Stage 5 above, dissolved in 3 ml of anhydrous methylene chloride. Purification is carried out by chromatography on silica with chloroform-ethyl acetate: 90-10 as eluant. In this way 133 mg of expected product (yellow gum) is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:32])[CH2:22][CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(prop-1-ynyl)pyrazole (2.1 g) in acetonitrile (40 ml) was added p-toluenesulphonic acid monohydrate (292 g) and the mixture was stirred at room temperature for 1 hour. p-Toluenesulphonic acid monohydrate (1 g) was then added and stirring continued overnight. Acetonitrile (20 ml) was added p-toluenesulphonic acid monohydrate (1 g) were added and stirring continued for 1 hour and then the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (500 ml) and extracted twice with ether (100 ml). The organic layer was separated, washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (70 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale brown solid, m.p. 167-169° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[NH2:34][OH:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([NH:34][OH:35])=[O:2])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: NO
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A slurry in methanol of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methyl ester (143 mg, 0.32 mmol), prepared as in Example 234, hydroxylamine hydrochloride (26 mg, 0.37 mmol) and potassium carbonate (106 mg, 0.77 mmol) was stirred at ambient temperature for 4 hours, then a solution of potassium hydroxide in methanol (0.33 mL) was added and stirring was continued overnight at ambient temperature. The reaction mixture was filtered and the filtrate was diluted with water and taken to pH 4. The aqueous phase was extracted with 3:1 chloroform-isopropanol. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by prep HPLC gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine hydroxamic acid (92 mg). 1H NMR (300 MHz, DMSO-d6) δ 10.58 (br s, 1H), 8.58 (d, 1H), 8.40 (d, 1H), 8.33 (d, 1H), 7.80 (dd, 1H), 7.60 (dd, 1H), 7.50 (m, 3H), 7.36 (m, 5H), 5.35 (s, 2H), 4.20 (m, 1H), 2.12 (m, 2H), 1.98 (s, 3H), 1.70 (m, 2H). MS (APCI) m/e 452 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([N:50]3[CH2:56][CH:55]4[O:57][CH:52]([CH2:53][CH2:54]4)[CH2:51]3)[CH:47]=[CH:48][CH:49]=2)O1.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:48]4[CH:49]=[CH:44][CH:45]=[C:46]([N:50]5[CH2:56][CH:55]6[O:57][CH:52]([CH2:53][CH2:54]6)[CH2:51]5)[CH:47]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(N3CC4CCC(C3)O4)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CC7CCC(C6)O7)c5)nc43)cc2)CCC1
Temperature: 160 °C
Yield: 95.5 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8-oxa-3-azabicyclo[3.2.1]octane (64.2 mg, 0.204 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.21 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DMF (2 mL) was heated at 160° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (5×) and brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=1:4→1:2→1:1→2:1→EtOAc) to afford desired product (62.1 mg, 94.7%) as orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH:15]1([N:21]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:23]4[C:24]([C:10]=3[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1)=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=4
Reactant: CCOC(=O)c1ccc(N(N)C2CCCCC2)cc1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Temperature: 85 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1.18 g, 5.65 mmol) and ethyl 4-(N-cyclohexylhydrazino)benzoate (1.14 g, 4.35 mmol) in acetic acid (11 ml) was stirred at 85° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, and conc. sulfuric acid (0.55 ml) was added to the reaction mixture. The mixture was stirred at 85° C. for 3 hr. The mixture was allowed to cool, and the reaction mixture was poured into water (230 ml) and extracted with a mixed solvent of ethyl acetate (200 ml) and ethanol (30 ml). The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Water (10 ml) and ethanol (10 ml) were added to the obtained crude product and the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (10 ml) of water:ethanol (1:1) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (0.97 g, yield 39%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:20])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)=O)C.[NH3:21]>CO>[Cl:20][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:21])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:10]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C)n1
Solvent: CO
Product: Cc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 4 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (137 mg, 0.468 mmol) was suspended in 7M ammonia in methanol (3 mL). After 4 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (123 mg, 100%) as an off-white solid which was used directly in the next step without purification. LCMS (EI/CI) m/z: 264 [M+H].
Reaction SMILES: C1(C=CC(C2C=CC=CC=2)=O)C=CC=CC=1.BrCCCC1C=CC=CC=1.[CH3:27][N+:28]([CH3:30])=[CH2:29].[I-].[ClH:32].CN(C)[C:35](C)([CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>>[ClH:32].[CH3:29][N:28]([CH2:30][CH:35]([CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][CH2:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37])[CH3:27]
Reactant: C=[N+](C)C
Reactant: CN(C)C(C)(C(=O)c1ccccc1)C(CCCc1ccccc1)c1ccccc1
Agent: BrCCCc1ccccc1
Agent: Cl
Agent: O=C(C=Cc1ccccc1)c1ccccc1
Product: CN(C)CC(C(=O)c1ccccc1)C(CCCc1ccccc1)c1ccccc1

Procedure:
The synthesis was carried out according to the procedure of Example 38. The chalcone derivative was reacted with 1-bromo-3-phenylpropane. The Eschenmoser salt was then added in an equimolar amount. The yield of (2RS)-(3RS)-2-dimethylamino-methyl-1,3,6-triphenylhexan-1-one hydrochloride was 0.9 g (44%).
Reaction SMILES: [N:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([O:40][CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:16]4[C:21]([C:22]5[CH:31]=[CH:30][C:25]6[N:26]=[C:27]([CH3:29])[O:28][C:24]=6[CH:23]=5)=[CH:20][N:19](COCC[Si](C)(C)C)[C:17]=4[N:18]=3)=[C:8]([O:46][CH3:47])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.ClC1N=C(OC2CCCC2)C2C(C3C=CC4N=C(C)OC=4C=3)=CN(COCC[Si](C)(C)C)C=2N=1.NC1C=CC(C(N2CC2)=O)=CC=1OC.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([O:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45]4)[C:16]4[C:21]([C:22]5[CH:31]=[CH:30][C:25]6[N:26]=[C:27]([CH3:29])[O:28][C:24]=6[CH:23]=5)=[CH:20][NH:19][C:17]=4[N:18]=3)=[C:8]([O:46][CH3:47])[CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)N2CC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cc(C(=O)N2CC2)ccc1N
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)c[nH]c2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Aziridin-1-yl(4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone. To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (4-amino-3-methoxyphenyl)(aziridin-1-yl)methanone (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-10% DCM in methanol) to afford the title compound (crude) as a yellow solid. The material was used in next step without further purification. MS (ESI) m/z 655.1 [M+1]+.