Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:4]=1[NH2:5].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[OH:1][CH2:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:4]=1[NH:5][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1ccc(N)c(CO)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(C)cc1CO)C(=O)OCC
Temperature: 110 °C
Yield: 87 %

Procedure:
A mixture of 2-(hydroxymethyl)-4-methylaniline (10.0 g) and diethyl ethoxymethylenemalonate (18.5 g) is heated at 110° C. for 1 h. Crystallization from ether/hexane afforded 19.5 g of the title compound. Physical characteristics: M.p. 92-95° C.; Anal. Found: C, 62.49; H, 6.88; N, 4.60.
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.O.[NH2:19][NH2:20]>C(O)C>[N:1]1([C:6]2([C:9](=[N:19][NH2:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 98 %

Procedure:
37.1 g (0.15 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 6 hours with 37.5 g (0.3 mol) of 80% strength hydrazine hydrate in 150 ml of ethanol. After removing the solvent by distillation in vacuo, 38.5 g (98%) of the title compound were obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)OC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 166, Step 3, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[N:20]4[N:21]=[C:22]([C:25]5[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=5)[CH:23]=[N:24][C:19]4=[N:18][CH:17]=3)[CH3:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[N:20]4[N:21]=[C:22]([C:25]5[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=5)[CH:23]=[N:24][C:19]4=[N:18][CH:17]=3)[CH3:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(C(=O)O)cc3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (24 mg, 0.57 mmol) was added to a solution of methyl 4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (47 mg, 0.115 mmol) in THF (0.5 mL) and methanol (0.5 mL) and water (0.2 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was adjusted with conc. HCl to pH 2. The volatiles were removed under reduced pressure to provide the crude product which was directly used in next step. LCMS: (M+H)=396.1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:14][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]=1[Br:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Add 1-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium carbonate (K2CO3, 40.0 g, 290 mmol) and benzyl bromide (49.6 g, 290, mmol) to DMF (800 mL). Stir the mixture at ambient temperature for 1 hour. Add water (400 mL) to precipitate the product. Collect the precipitate and wash the filter cake with heptane (3×125 mL) then dry to provide 83.7 g of 2-benzyloxy-1-bromo-6-methoxy-naphthalene (86.2%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[N:8][OH:9].O.[OH-].[K+]>C(OC(O)C)C>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[O:9][N:8]=1
Reactant: COc1ccccc1C(=NO)c1sccc1Br
Agent: CCOC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1noc2ccsc12
Reaction time: 0.17 h

Procedure:
A solution of 12.0 g of (3-bromothien-2-yl) (2-methoxyphenyl)methanone oxime in 220 ml of ethoxyethanol was combined with 15 ml of water containing 4.3 g of potassium hydroxide pellets (85%) and the mixture was stirred at 110° for 10 minutes and thereafter 0.28 g of cuprous chloride was added. Stirring was maintained at this temperature under nitrogen for one hour.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:24](O)(=[O:26])C>O>[CH:24]([C:3]1[C:4]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[N:6][C:5]=2[NH:1][CH:2]=1)=[O:26]
Reactant: COC(=O)c1ccnc2[nH]ccc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: COC(=O)c1ccnc2[nH]cc(C=O)c12
Temperature: 25 °C

Procedure:
Methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (500 mg, 2.84 mmol) and hexamethylenetetramine (796 mg, 5.68 mmol) were combined in water (8 mL) and glacial acetic acid (16 mL) and heated at 100° C. overnight then cooled to room temperature. The reaction mixture was extracted with ethyl acetate and the organics were dried over MgSO4 and concentrated in vacuo to give a residue. Purification of the residue by silica gel chromatography (50% EtOAc/Hexanes) gave the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H, J=4.8 Hz), 7.48 (d, 1H, J=4.8 Hz), 5.74 (d, 1H, J=6.8 Hz), 3.91 (s, 3H), 2.78 (s, 3H). [M+H] found 205.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][CH:5]=1.[CH3:15][I:16]>C(#N)C>[I-:16].[CH3:1][N+:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][CH:5]=1
Reactant: CI
Reactant: Cc1cccc2[nH]cc(CN(C)C)c12
Solvent: CC#N
Product: Cc1cccc2[nH]cc(C[N+](C)(C)C)c12
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl-(4-methyl-1H-indol-3-ylmethyl)-amine (20 g, 98 mmol) is suspended in acetonitrile, and warmed to completely dissolve the material. The reaction is cooled to room temperature and then methyl iodide (9.1 mL, 147 mmol) is added dropwise to the reaction. The reaction is covered with foil and then stirred at room temperature overnight. The reaction is then filtered and the filtrate evaporate in vacuo to give an oil that is taken up in acetonitrile. The white solid is then triturated with acetonitrile and ether, and combined with the original solid to give the title compound that is used without further purification (30 g, 87 mmol, 88%) LC/MS (M++1): 347.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4](I)[CH:3]=1.C([Li])CCC.CON(C)[C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4]([C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH:3]=1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Reactant: CC1(C)COC(c2ccc(Cl)cc2I)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(CCC(=O)c1cc(Cl)ccc1C1=NC(C)(C)CO1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-(4-chloro-2-iodophenyl)-4,4-dimethyl-4,5-dihydrooxazole (3.3 g, 9.7 mmol) in dry THF (30 mL) at −78° C. was added n-butyl lithium (2.5 M in hexane, 4.0 mL, 10.0 mmol) drop wise. After stirring for 30 min, a solution of tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (2.0 g, 8.1 mmol) in dry THF (5 mL) was added. The reaction mixture was warmed slowly to 0° C. then stored in refrigerator (4° C.) over night. The reaction was then warmed to room temperature and stirred 7 h. The reaction was quenched with 1N HCl, diluted with brine and ethyl acetate. After separation, the organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to give product (1.2 g, 38%). 1H NMR (CD3OD) δ 7.75 (d, J=7.6 Hz, 1H), 7.55-7.60 (m, 2H), 4.10-4.20 (m, 2H), 3.58 (t, J=6.8 Hz, 2H), 3.05-3.15 (m, 2H), 2.88 (s, 3H), 1.43 (s, 9H), 1.35 (s, 6H); MS EI m/z 395 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([C:17]([F:20])([F:19])[F:18])([OH:16])CO.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>CO>[F:20][C:17]([F:18])([F:19])[C:13](=[O:16])[CH2:12][C:11]([C:4]1[CH:5]=[C:6]([S:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:22])[CH3:21]
Reactant: COc1ccc(SC)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CO
Product: COc1ccc(SC)cc1C(C)(C)CC(=O)C(F)(F)F
Yield: 69 %

Procedure:
To a solution of 4-(2-methoxy-5-methylsulfanylphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol (1.5 g, 5.3 mmol) in 25 mL of methanol was added 2.4 g of lead (IV) acetate (Pb(OAc)4) and the reaction mixture was stirred until TLC indicated the reaction was complete, after several hours. The reaction mixture was then filtered through a bed of diatomaceous earth and the filtrate was concentrated in vacuo to afford 1.12 g (83.8% yield) of 1,1,1-trifluoro-4-(2-methoxy-5-methylsulfanylphenyl)-4-methylpentan-2-one.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(N)cc3)ncnc2n1
Yield: 74.9 %

Procedure:
The product of Example 10D (2.78 g, 4.152 mmol) was treated with trifluoroacetic acid (25 mL) in methylene chloride (25 mL) at room temperature for 30 minutes. The solvents were removed under vacuum by rotary evaporation and the residual oil taken up in ethyl acetate (400 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL), water (2×100 mL), and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with 3% methanol/methylene chloride and dried in vacuo to afford the title compound as a light beige solid (1.77 g, 75%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (d, J=6.99 Hz, 6 H) 3.09-3.31 (m, 1 H) 5.03 (s, 2 H) 6.57 (d, J=8.82 Hz, 2 H) 6.78 (d, J=8.82 Hz, 2 H) 6.83 (d, J=8.82 Hz, 1 H) 7.53 (d, J=8.82 Hz, 2 H) 7.60 (d, J=8.82 Hz, 1 H) 7.75 (d, J=9.19 Hz, 2 H) 7.85 (dd, J=8.46, 2.21 Hz, 1 H) 8.16 (d, J=2.21 Hz, 1 H) 8.62 (s, 1 H) 8.84 (d, J=8.46 Hz, 1 H) 10.00 (s, 1 H) 10.29 (s, 1 H); MS (ESI+) m/z 569/571 (M+H)+, MS (ESI−) m/z 567/569 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cccc(CNCC(=O)OC(C)(C)C)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(CN(CC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}pyridine-2-carboxylate (2.81 g) in tetrahydrofuran (30.0 mL) were added water (30.0 mL) and sodium hydrogen carbonate (962 mg), and then benzyl chloroformate (1.47 mL) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature overnight and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylate (3.27 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([OH:24])([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO>[CH2:20]([C:19]([C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][C:9]([OH:8])=[CH:18]2)=[CH:13][CH:14]=1)([OH:24])[CH2:22][CH3:23])[CH3:21]
Reactant: CCC(O)(CC)c1ccc2ccc(OCc3ccccc3)cc2c1
Reactant: [H][H]
Solvent: CCO
Product: CCC(O)(CC)c1ccc2ccc(O)cc2c1
Yield: 93.9 %

Procedure:
Treat a mixture of 3-(7-benzyloxynaphthalen-2-yl)pentan-3-ol (1.45 g, 4.53 mmol) and 5% Pd/Al2CO3 (0.044 g) in EtOH (725 mL) with hydrogen at 60 psi for 8 h at RT. Remove the catalyst by filtration and concentrate the filtrate to give the title compound as a yellow oil (0.98 g, 94%). MS (ES) m/e 229 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 97.6 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28, 0.33 g, 1.1 mmol), (s)-1-(4-fluoro-phenyl)-ethylamine (0.16 g, 1.2 mmol) and DIEA (0.21 ml, 1.2 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.43 g, 97%). 1H NMR (400 MHz) δ 12.09, 12.05 & 11.64 (s, 1H), 10.94, 10.87 & 10.72 (s, 1H), 8.98, 8.76 & 8.70 (d, J=7.6 Hz, 1H), 8.16 & 8.11 (d, J=9.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.22-7.10 (m, 2H), 6.25 & 6.04 (d, J=9.6 Hz, 1H), 6.23 & 5.86 (d, J=13.6 Hz, 1H), 5.31, 5.21 & 4.89 (m, 1H), 4.71, 4.59 & 4.27 (m, 1H), 1.52 (m, 3H), 1.26 (m, 6H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[O:27]([CH2:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH2:34][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)COc1ccccc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with phenoxyacetyl chloride under the conditions described in example 2 to yield 88% of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 22 %

Procedure:
Prepared analogously to Example 149a from 3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 22% of theory, Rf value: 0.68 (silica gel; dichloromethane/methanol=19:1)
Reaction SMILES: N1C=CC=CC=1.Cl.[CH2:8]([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2[S:13][C:12]=1[C:20]([Cl:22])=[O:21])[CH2:9][CH3:10].[CH3:23][NH:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.CN(C1C=CC=CN=1)C>O.CN(C)C=O>[ClH:22].[Cl:31][C:29]1[CH:30]=[C:25]([N:24]([CH3:23])[C:20]([C:12]2[S:13][C:14]3=[N:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[CH2:8][CH2:9][CH3:10])=[O:21])[CH:26]=[C:27]([Cl:32])[CH:28]=1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: CNc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCC1=C(C(=O)N(C)c2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Temperature: 70 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
In the mixture of 30 ml of pyridine and 3 ml of dimethylformamide was suspended 938 mg of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 587 mg of N-methyl-3,5-dichloroaniline, and 40 mg of dimethylaminopyridine, followed by stirring at 70° C. for 18 hours. The reaction mixture was cocentrated and to the mixture was added water. The organic layer was extracted with chloroform. The extact was washed with 5% sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the solution was added saturated hydrogenchloride diethylether solution. The mixture was stirred at room temperature, followed by removing the solvent under reduced pressure. The residue was purified by column chromatography (silica gel: 45 g) using a mixed solvent of chloroform and methanol (20:1 by volume) as an eluent. The resulting substance was treated with saturated hydrogenchloride diethylether solution and recrystallized from a mixed solvent of ethanol and diethylether to obtain 461 mg of the titled compound.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H:2]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)=[O:35])[CH2:27][CH2:26]1.O.OO>O1CCCC1>[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH2:46][CH3:2])=[O:44])=[CH:38][CH:37]=2)[OH:35])[CH2:27][CH2:26]1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1ccc([C@@H](O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve (−)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, methyl ester (3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stir at room temperature for 3 days and cool to 0° C. Add water (1 mL) and 30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylene chloride (30 mL) and wash with brine (30 mL), then aqueous sodium hydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([C:47]([OH:49])=O)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)([CH3:27])[CH3:26].[CH2:50]([N:52](CC)[CH2:53]C)[CH3:51].C(NC)C>CN(C)C=O>[CH2:50]([N:52]([CH3:53])[C:47]([C:41]1([C:38]2[CH:39]=[CH:40][C:35]([O:34][CH:31]3[CH2:32][CH2:33][N:28]([CH:25]([CH3:26])[CH3:27])[CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)=[O:49])[CH3:51]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Reactant: CCN(CC)CC
Agent: CCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C)C(=O)C1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (286 mg, 0.75 mmol) was added to a solution of 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol) in N,N-dimethylformamide (6 mL). Then triethylamine (243 μL, 1.74 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Ethylmethylamine (500 μL, 5.8 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (2×75 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (80 mg, 35%). 1H NMR (400 MHz, CD3OD) δ 1.06-1.25 (m, 9H), 1.90-2.02 (m, 4H), 2.08-2.12 (m, 2H), 2.25-2.28 (m, 2H), 2.58 (m, 2H), 2.87 (m, 3H), 2.95 (m, 2H), 3.09-3.12 (m, 3H), 3.71-3.76 (m, 2H), 3.82-3.86 (m, 2H), 4.53 (m, 1H), 6.98 (d, 2H), 7.20 (d, 2H).