Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[N:3]=1.[C:15]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:15]([CH:19]1[CH2:24][CH2:23][C:22]2([O:14][CH:11]([CH2:10][NH:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:12][O:13]2)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: Cc1cc(C)nc(NCC(O)CO)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C)nc(NCC2COC3(CCC(C(C)(C)C)CC3)O2)n1
Yield: 90 %

Procedure:
3-(4,6-dimethylpyrimid-2-ylamino)-propane-1,2-diol (4.0 g, 20 mmol), 4-t-butyl cyclohexanone (3.08 g, 20 mmol) and p-toluenesulfonic acid (4.3 g, 22 mmol) in 50 ml benzene were refluxed on a water trap for 1 hour. The reaction mixture was washed twice with saturated aqueous sodium carbonate (50 ml), dried with magnesium sulphate and evaporated in vacuum. Kugelrohr--distillation of the resulting oil yielded 6.0 g of a colourless oil (b.p. 200° C./0.2 mbar) which was recrystallised from light petroleum to yield 5.0 g of colourless crystals (m.p. 121°-124° C.). GLC-MS analysis indicates an approximately 1:1 mixture of diastereoisomers (cis/trans).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7](S(C)(=O)=O)[N:6]=1.C(OC([N:40]1[CH2:44][CH2:43][C@@H:42]([NH2:45])[CH2:41]1)=O)(C)(C)C>C(#N)C>[CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7]([NH:45][C@@H:42]2[CH2:43][CH2:44][NH:40][CH2:41]2)[N:6]=1
Reactant: Cc1ccc(-c2nnc[nH]2)cc1Nc1nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c1C#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CC#N
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1nc(N[C@@H]2CCNC2)nc(N(C)CC(C)(C)C)c1C#N
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 4-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamino]-pyrimidine-5-carbonitrile (10 mg, 0.022 mmol) and 1-tert-butoxycarbony-3(R)-amino-pyrrolidine (0.08 g, 0.4 mmol) in 2 mL of acetonitrile was heated with stirring at 80° C. for 18 h. Volatiles were the removed in vacuo and the product was purified by flash chromatography.
Reaction SMILES: [OH:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:13][C:12]1[C:2]([O:1][CH:15]([CH3:17])[CH3:16])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(OC(C)C)c(I)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 500 mg (1.71 mmol) of ethyl 6-hydroxy-5-iodonicotinate (from Step A) in 10 mL of DMF were added 330 mg (1.96 mmol) of 2-iodopropane and 1.67 g (5.11 mmol) of cesium carbonate. After stirring at 50° C. for 16 h, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with brine (3×20 mL), dried over MgSO4, and concentrated. Chromatography on a Biotage 25+M cartridge using 4:1 v/v hexanes/EtOAc as the eluant to afford 210 mg (37%) of a white solid as the title compound: 1H NMR (500 MHz, CDCl3) δ 1.40 (m, 9H), 4.37 (q, J=7.1, 2H), 5.37 (m, 1H), 8.59 (d, J=2.1, 1H), 8.74 (d, J=2.0, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]3OCC[O:14]3)[N:10]=[C:9]2[CH3:18])=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:18])=[CH:6][CH:7]=1
Reactant: Cc1nc(C2OCCO2)cn1-c1ccc(Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C=O)cn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole (1.05 g, 3.97 mmol) and camphorsulfonic acid (92 mg, 0.40 mmol, 0.1 equiv) in THF (26.5 mL) and water (13.3 mL) was heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde (0.600 g, tan solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 2.40 (s, 3H). MS m/z 221.0 (M+H)+; Rt-0.47 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:30])[CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:17]=[C:18]([Cl:30])[C:19]=1[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2-c2ccc(F)cc2)CC1
Temperature: 10 °C
Yield: 44 %

Procedure:
150 mg of 4-(5-Bromo-3-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (181) were dissolved in a mixture of 9 ml of dioxane and 3 ml of water, 47 mg of 4-fluoro-benzene-boronic acid, 47 mg of Na2CO3 and 40 mg of Pd(PPh3)4 were added and the resulting mixture was heated to 10° C. for 6 h. The solvent was removed in vacuo and the residue subjected to chromatography on a HPLC system. Yield: 44%
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:18]=[C:19]([C:23]3[N:28]=[C:27]([C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[CH:26]=[C:25](Cl)[N:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C>[CH3:36][O:35][C:32]1[N:31]=[C:30]([O:37][CH3:38])[C:29]([C:27]2[CH:26]=[C:25]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:24]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[CH:18]=3)[N:28]=2)=[CH:34][N:33]=1
Reactant: COc1ncc(-c2cc(Cl)nc(-c3cccc(NC(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)c(OC)n1
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1ncc(-c2cc(N3CCOCC3)nc(-c3cccc(NC(=O)C4CCNCC4)c3)n2)c(OC)n1
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonylpiperidin-4-ylcarbonylamino)phenyl]-6-chloro-4-(2,4-dimethoxypyrimidin-5-yl)pyrimidine (0.072 g), morpholine (0.056 g) and acetonitrile (2.5 ml) was stirred under an atmosphere of nitrogen and heated to 100° C. for 5 minutes using microwave radiation. The reaction mixture was evaporated. Toluene was added and the mixture was re-evaporated. Trifluoroacetic acid (3 ml) was added to the material so obtained and the mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated. Toluene was added and the mixture was re-evaporated and the residue was purified by column chromatography on an ‘Isolute SCX’ column (1 g) by initially washing the column with methylene chloride and then with methanol (5 ml) followed by elution with a 7M methanolic ammonia solution. The material so obtained was dried under vacuum. There was thus obtained the title compound as a solid (0.019 g); NMR Spectrum: (CDCl3) 1.68-1.84 (m, 2H), 1.91-2.0 (m, 2H), 2.37-2.5 (m, 1H), 2.63-2.76 (m, 2H), 3.14-3.27 (m, 2H), 3.74-3.91 (m, 8H), 7.07 (s, 1H), 7.12 (s, 1H), 7.42 (t, 1H), 8.03 (d, 1H), 8.21 (d, 1H), 8.31 (s, 1H), 9.37 (s, 1H); Mass Spectrum: M+H+ 506.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[O:6][C:7]=1[CH3:8].[O:18]=[CH:19][C:20]1[CH:28]=[CH:27][C:25]([OH:26])=[C:22]([O:23][CH3:24])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([CH:28]=[CH:27][C:25]=1[O:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[O:6][C:7]=1[CH3:8])[CH:19]=[O:18]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccc([N+](=O)[O-])c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (2.67 g), vanillin (1.52 g), anhydrous potassium carbonate (1.38 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, and filtered through a silica gel column. The filtrate was concentrated and the residue was washed with diethyl ether-hexane to give 3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}benzaldehyde as colorless crystals (3.58 g, yield 97%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 179-180° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[NH:29]1)=[O:27])[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([N:29]2[CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32][N:28]2[C:26]([O:25][CH2:22][CH:23]=[CH2:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OC1CCCCO1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
(2R)-3-Cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl fluoride (784 mg, 2.6 mmol) was added into the solution of 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidine carboxylic acid (677 mg, 3.38 mmol) and Hunig's base (1811 μl, 10.40 mmol) in N,N-dimethylformamide (DMF) (11.1 ml). The reaction was stirred for 5 hrs at ambient temperature. The reaction was purified by RP-HPLC to give 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (428 mg, 0.889 mmol, 34% yield). MS (ES+) m/z 482.0 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:30].C(O)C>C(OCC)C>[IH:30].[CH:23]([O:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)([CH3:25])[CH3:24]
Reactant: CC(C)OCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CC(C)OCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.63 g, 1.57 mmol), aqueous hydriodic acid (5 mL, 57%), and ethanol (10 mL). Heat to reflux. After 1 hour, cool to ambient temperature and pour the reaction mixture into diethyl ether (350 mL) and stir to give a solid. After 1 hour, collect the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:13]([Cl:27])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:27][C:13]1[CH:12]=[N:11][C:10]2=[N:15][C:14]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([O:26][CH2:2][C:3]3[CH:4]=[C:5]([NH:9]2)[CH:6]=[CH:7][CH:8]=3)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(CCCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCCCc1cccc(c1)OCc1cccc(c1)N2
Yield: 19.5 %

Procedure:
To a solution of 3-{3-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]propyl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was added a solution of sodium hydroxide in water (0.893 mL, 0.50 M). The resultant solution was stirred at rt for 16 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give the desired product as a white powder (8 mg, 20%). LCMS for C20H20ClN4O (M+H)+: m/z=367.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.75 (s, 1H), 7.26 (m, 1H), 7.17 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 6.88 (m, 1H), 6.70 (m, 1H), 6.60 (m, 1H), 5.17 (s, 2H), 3.48 (t, J=7.6 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H), 1.91 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH3:13]I>O1CCCC1>[CH3:13][CH:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCC(=O)CC(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(methyloxy)-3-oxobutanoate (2.0 g, 13.69 mmol) was dissolved in tetrahydrofuran (THF) (14 mL), cooled in an ice bath and treated portionwise with 60% sodium hydride in mineral oil (0.547 g, 13.69 mmol). The resulting mixture was allowed to warm to room temperature over 25 minutes and then treated dropwise with a solution of methyl iodide (0.856 mL, 13.69 mmol) in tetrahydrofuran (THF) (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed with water. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (SP4, 40+M) eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil. (1.01 g);
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: CN(C)C=O
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 g, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.006 mole), and methyl iodide (0.78 g, 0.0055 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.06 g, yield: 84.0%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:30][OH:31])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C=NO)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium acetate (1.0664 g) in acetic acid (20 ml) was stirred at room temperature for an hour to form isopropyl 2-methyl-4(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was heated at 95° to 100° C. for 6 hours. After removal of the acetic acid, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (3.69 g) was chromatographed on a column of silica-gel (100 g), and eluted with a mixture of benzene and ethyl acetate (5:1, v/v) to give an oil of isopropyl 2-methyl-4(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (2.0 g), which was left in a refrigerator for several days to crystallize. Recrystallization from methanol gave pure crystals, m.p. 175.5°-176.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]([CH3:15])[C@H:11]([NH:16]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[Pd].CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]([CH3:15])[C@H:11]([NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)CC[C@H]1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)CC[C@H]1N

Procedure:
Racemic cis 4-amino-5-methyl-azepane-1-carboxylic acid tert-butyl ester was prepared in the same manner from racemic cis 4-benzylamino-5-methyl-azepane-1-carboxylic acid tert-butyl ester. In this instance, 1 atm H2 was used instead of 55 psi, Pd/C was used instead of Pd(OH)2/C, EtOAc was used instead of EtOH, and the HCl treatment was omitted.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
25.0 mg (1.00 mmol) 95% sodium hydride were given to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 3.0 ml DMF and stirred for 30 min. 346 mg (1.00 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. for 24 h. After cautious addition of 10 ml water the mixture was diluted to 60 ml by further addition of water and stirred for 30 min. The resulting precipitate was washed with 3×10 ml water, 2×10 ml methanol/water, diethyl ether and dried to yield 440 mg (84%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=O.CCO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A round bottomed flask was charged with palladium on carbon (327 mg, 0.308 mmol) and a stirbar. Ethyl 3-(2-nitrophenylamino)butanoate (776 mg, 3.08 mmol) in 1:1 EtOH:EtOAc (40 mL) was added, and the flask was evacuated and purged with hydrogen three times. Stirred at room temperature for 3 h. The mixture was filtered and concentrated to yield ethyl 3-(2-aminophenylamino)butanoate as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[CH:42]=[CH:41][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:18][CH:17]=1>C(O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:41][CH:42]=1
Reactant: Clc1ncccn1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2c2ncccn2)cc1

Procedure:
0.013 ml of triethylamine and 6.3 mg of 2-chloro-pyrimidine were added in order to an ethanol (2 ml) solution of 17.1 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was heated under reflux for 3 hours. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.