Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5].[OH-].[Na+].[F:19][C:20](=[C:24]([F:26])[F:25])[CH2:21][CH2:22]Br>CS(C)=O.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:22][CH2:21][C:20]([F:19])=[C:24]([F:26])[F:25])=[O:10])[CH3:8])=[O:5]
Reactant: FC(F)=C(F)CCBr
Reactant: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)OCCC(F)=C(F)F
Temperature: 20 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
6.4 g (28 mmol) of N-(2,6-difluorobenzoyl)alanine are dissolved in 50 ml of dimethyl sulphoxide (DMSO) and admixed with 1.2 g (31 mmol) of sodium hydroxide dissolved in a little water. 5.7 g (30 mmol) of 3,4,4-trifluorobut-3-enyl bromide are subsequently added, and the mixture is stirred at 20° C. overnight. The mixture is then poured into water and the product is extracted with ethyl acetate and subsequently purified by column chromatography over silica gel using the system ethyl acetate. In this manner, 2.5 g (26.5% of theory) of 3,4,4-trifluorobut-3-enyl N-(2,6-difluorobenzoyl)-alaninate are obtained as an oil. log p (pH 2)=2.42.
Reaction SMILES: C[NH:2][C:3]1[C:4](=[CH:8][C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])[C:5]([OH:7])=[O:6].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=C[CH:26]=1>C(Cl)(Cl)Cl>[CH3:26][O:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:3]=1[NH:2][S:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNc1c(C)cc(C)cc1C(=O)O
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 2.00 g (0.011 mmol) of methyl 3,5-dimethylanthranilic acid in 10.0 mL of pyridine was added 2.17 (0.011 mmol) of 4-fluorobenzenesulfonyl chloride. The reaction mixture was stirred for 24 h at room temperature and then diluted with chloroform and washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes and the resulting solid was filtered and dried to provide 3.09 g (82%) of the desired product as a white solid. Electrospray Mass Spec: m/z 338.3 (M+H)+.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([CH:5]([CH2:8][CH3:9])[CH:6]=O)[CH3:4]>>[CH2:3]([C:5](=[CH:6][N:2]=[CH:6][CH:5]([CH2:8][CH3:9])[CH2:3][CH3:4])[CH2:8][CH3:9])[CH3:4]
Reactant: CCC(C=O)CC
Reactant: [NH4+]
Agent: [OH-]
Product: CCC(=CN=CC(CC)CC)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a sample of 250 grams of 28% ammonium hydroxide was added 215 grams of 2-ethylbutyraldehyde and the heterogeneous mixture was stirred for 18 hours at ambient temperature. The resulting organic layer was separated, and after drying, slowly distilled at atmospheric pressure to yield 148.8 grams of 3,7-diethyl-5-azanona-3,5-diene.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17](I)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Br:1][C:2]1[S:3][C:4]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c([N+](=O)[O-])c2)sc1Br
Yield: 72 %

Procedure:
A solution of 2 (2.00 g, 3.82 mmol), phenylacetylene (0.47 mL, 4.28 mmol), Pd(PPh3)2Cl2 (137 mg, 0.19 mmol), K2CO3 (542 mg, 3.92 mmol), and Et3N (0.55 mL, 3.95 mmol) in DMF (5 mL) was stirred for 24 h at room temperature. Water (10 mL) was added to the mixture and then extracted with Et2O (3×30 mL). The combined organic layer was washed with brine (3×15 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 3 as a yellow amorphous solid (1.37 g, 72%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.52 (s, 1H), 7.43-7.37 (m, 3H), 4.19 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.93, 169.64, 149.51, 142.13, 136.97, 136.36, 135.90, 135.24, 132.92, 132.52, 130.11, 128.82, 125.57, 124.25, 122.73, 122.06, 101.10, 84.72, 61.75, 35.26, and 14.42.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14])[CH3:2].[OH-].[Na+].[Br:17]Br>O>[Br:17][C:6]1([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[O:14])[NH:8][C:9](=[O:13])[NH:10][C:11]1=[O:12]
Reactant: BrBr
Reactant: CCOCCC1C(=O)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (27.8 g, 139 mmol) (from Preparation 2A) and 1.5 L of water was added 1M sodium hydroxide solution (140 mL) and bromine (7.2 mL, 22.2 g, 139 mmol) at 0° C. After warming to room temperature, the mixture was stirred for 48 hours, filtered, and the solids were washed with water, then ether, then hexanes and dried in vacuo, afforidng 23 g of 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione. 1H NMR (CDCl3): 8.37 (bs, 2H), 3.53 (t, 2H, J=7.0 Hz), 3.35 (q, 2H, J=6.5 Hz), 2.99 (t, 2H, J=7.0 Hz), 1.05 (t, 3H, J=6.5 Hz) ppm. MS (m/z, APCI): 468 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][O:4][CH2:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:9]([NH:16][C@H:7]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Racemic 3-methyl-tetrahydro-pyran-4-one (1 g, 8.761 mmol) was dissolved in DCM. Benzylamine (1.5 mL, 13.75 mmol) and sodium triacetoxyborohydride (95%, 3.3 g, 14.89 mmol) were added and the resulting suspension was stirred at RT overnight. The reaction mixture was washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The remaining yellow liquid was purified by SiO2 chromatography (120 g SiO2, DCM/(DCM:MeOH:NH4OH 60:10:1) 92% DCM) to give 1.8 g of racemic cis benzyl-(3-methyl-tetrahydro-pyran-4-yl)-amine as a light yellow oil (>95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH2:10][C:9]([F:12])(F)[C:8]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:12])[C:8]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:7][C:3]=1[C:4]([O:6][CH2:27][CH:29]1[O:31][CH2:30]1)=[O:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(C2=CC(C(=O)[O-])=C(Cl)CC2(F)F)c1=O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OCC3CO3)c(Cl)cc2F)c1=O

Procedure:
3.0 g of potassium 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate and 0.6 ml of epichlorohydrin are heated at 70° C. for 3 hours in 25 ml of dimethylformamide. Thereafter, the reaction solution is added to 500 ml of water and adjusted to pH 10 to 11 with a small amount of saturated potassium carbonate solution. It is extracted twice with 300 ml of ethyl acetate. The organic phases are washed twice with 200 ml of water, dried over anhydrous magnesium sulphate and concentrated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane. There is obtained 2,3-epoxypropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate as a pale yellow oil, 1H-NMR(D6 -DMSO, 400 MHz): 2.73 (m,1H), 2.85 (m,1H), 32 (m,1H), 3.42 (s,3H), 4.10 (m,1H), 4.69 (m,1H), 6.62 (s,1H), 7.92 (d,1H), 8.11 (d,1H), mass spectrum (m/e): M+ 422(16).
Reaction SMILES: CC[CH2:3][C:4]([O:6][C:7]([CH2:9][CH2:10][CH3:11])=[O:8])=O.[CH2:12](O)[CH3:13].[CH2:15]([NH2:17])C>O>[CH3:15][NH:17][C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:7]([O:6][CH2:4][CH3:3])=[O:8]
Reactant: CCN
Reactant: CCO
Reactant: CCCC(=O)OC(=O)CCC
Solvent: O
Product: CCCC(=CC(=O)OCC)NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A solution of 31.64 g(0.2 mol) ethyl butyryl acetate and 5 mol of ethanol is added dropwise over a period of 5 min. to a solution of 38.7 g(0.6 mol) ethylamine (70% in water) and 50 ml of water (exotherm from 28° C. to 33° C. observed). The mixture is stirred at room temperature for 18 hrs. and is extracted with three 100 ml portions of methylene dichloride (MDC). The methylene dichloride extract is dried over magnesium sulfate and concentrated in vacuo to afford 30.7 g(83% yield) of product, a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:14]>CC1C=CC(C)=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:15][C:13]#[N:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCC2=O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccc(C)cc1
Product: COc1cccc2cc(CC#N)oc12
Yield: 68.5 %

Procedure:
A mixture of 14.16 g of 7-methoxy-3-benzofuranone, 39.4 g of cyanomethylenetriphenylphosphorane and 70 ml of p-xylene was heated at reflux under nitrogen for 16 hours. The solvent was removed, the solid washed repeatedly with ether and the product obtained on removal of the solvent from the ether washings sublimed (145° bath, 1 micron). Crystallization of the sublimate from 20 ml of isopropyl alcohol gave 11.06 g (69% yield) of 7-methoxy-3-benzofuranacetonitrile. Nmr spectrum (in CDCl3): τ2.4 (t, J=1-2 Hz, 1); 2.8-3.3 (m, 3); 6.0 (s, 3) and 6.3 (d, J=1-2 Hz, 2).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][OH:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:28][CH:29]=[O:30])[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[CH:17][CH:18]=1)#[N:12]
Reactant: CN(C)C(=O)N(CCO)CCCc1ccc(C#N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)N(CC=O)CCCc1ccc(C#N)cc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Oxalyl chloride (4.84 g, 0.038 mol) was added dropwise to a stirred solution of DMSO (5.9 g, 0.0763 mol) and dichloromethane (100 mL) at −78° C. After 15 min at the same temperature, 1-[3-(4-cyanophenyl)propyl]-1-(2-hydroxyethyl)-3,3-dimethylurea (7 g, 0.0254 mol) in dichloromethane was added and stirring continued for 3 h under a nitrogen atmosphere. Triethylamine (12.8 g, 0.127 mol) was added (dropwise), and the reaction mixture was then warmed slowly to −30° C. The reaction mixture was quenched with 10% citric acid (aq.) and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to yield 6.5 g of the crude title compound, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3ccc(OC(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a second equivalent of benzoyl chloride was added with continued stirring overnight. The reaction was diluted with ethyl acetate and the phases were separated. The organic layer was washed with 1N sodium hydroxide, water and brine; then it was dried over magnesium sulfate and concentrated to an oil which solidified (0.065 g, 69%). A sample recrystallized from ether/hexane as a light pink solid was submitted for analysis: mp 82°-82.5° C. Analysis calculated for C22H22N2O2 ·0.25 H2O: C, 75.30; H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(COC(=O)c2ccccc2)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.95 g) in pyridine (25 ml) was dropwise added a solution of benzoyl chloride (2.0 g) in methylene chloride (5ml) over 5 minutes at 5° to 6° C. with stirring. The resultant mixture was stirred for 15 minutes at the same temperature and then at room temperature for 2 hours, and followed by stirring at 50° C. for an hour and a half. After the reaction was over, the pyridine was distilled off and to the residue was added ethyl acetate and water. The ethyl acetate layer was separated, washed with dil. hydrochloric acid twice and then aqueous solution of sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed and the residue was soon crystallized by treating with diethyl ether and collected by filtration. These crude crystals were washed with a mixture of diethyl ether and a small amount of ethyl acetate to give crystals, which was recrystallized from ethyl acetate (25 ml) to give powders of diethyl 2-methyl-4-(2-nitrophenyl)-6-benzoyloxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 156° to 157° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12](=O)(O)[O-].[Na+].[CH3:17][C:18]([CH3:20])=[O:19]>O>[C:2](=[C:1]1[CH2:11][CH2:20][C:18](=[O:19])[CH2:17][CH2:6]1)([CH3:12])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Reactant: CC(C)=O
Agent: [Na+]
Solvent: O
Product: CC(C)=C1CCC(=O)CC1
Temperature: 25 °C
Yield: 92 %

Procedure:
p-Toluenesulfonic acid (31.16 g, 164 mmol) was added to a solution of ketal (2, 23.0 g, 126 mmol) in acetone (2.3 L) and water (138 mL). The reaction mixture was heated to reflux and maintained at reflux for 3.5 h. The mixture was cooled to room temperature, treated with saturated sodium bicarbonate (60 mL) and concentrated under vacuum. The resulting oily residue was extracted with ethyl acetate (2×130 mL), washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum to give an oil. Weight: 16 g. Weight yield: 92%. 1H-NMR (400 MHz, CDCl3): δ 1.69 (s, 6H), 2.35 (t, 4H), 2.50 (t, 4H). MS (APCI method): No molecular ion peak was observed (Note: 1H-NMR showed the presence of ˜2% of ketal 2 but used without purification).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7]>CO.O1CCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 2.0 M solution of dimethylamine (0.5 mmol) in methanol was added to a solution of 2-bromo-1-(4-bromophenyl)ethanone (114.5 mg, 0.41 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 15 min. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 0:100) to give 84.7 mg (yield 86%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](O)=[O:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN(C=O)C>O>[CH3:14][C:9]1([CH3:15])[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8]1
Reactant: CC(C)(CC(=O)O)Nc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)Nc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
An round bottomed flask was charged with crude 3-(2-aminophenylamino)-3-methylbutanoic acid (2.19 g, 10.52 mmol), HOBT (1.932 g, 12.62 mmol), EDC (2.419 g, 12.62 mmol), and a stirbar. DMF (20 mL, 0.5 M) was added, and the solution was stirred at rt overnight. The solution was diluted with water, extracted three times with methylene chloride, dried with sodium sulfate, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate/1% isopropanol) to yield 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a yellow amorphous solid (0.697 g, 3.66 mmol, 35%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]([CH3:20])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:6]#[N:7].S(=O)(=O)(O)[OH:23].C(Cl)[Cl:28].[OH-].[Na+]>O>[ClH:28].[CH3:21][N:2]([CH3:1])[C@H:3]([CH3:20])[CH2:4][C@@:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:6]([NH2:7])=[O:23]
Reactant: ClCCl
Reactant: CC(CC(C#N)(c1ccccc1)c1ccccn1)N(C)C
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](C[C@@](C(N)=O)(c1ccccc1)c1ccccn1)N(C)C
Product: Cl
Reaction time: 0.17 h

Procedure:
A mixture of 4-dimethylamino-2-phenyl-2-(2-pyridyl)-valeronitrile (50.0 g), water (2.74 g) and sulfuric acid (50 ml) was reacted at 100-105° C. for 2 hours. The reaction mixture was then cooled, diluted with cold water (100 ml) and poured into a mixture of methylene chloride (400 ml) and water(500 ml). The aqueous layer was adjusted to pH 12.5 with 24% aqueous sodium hydroxide solution. The organic layer was taken, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. To this were added isopropyl alcohol (75 ml), acetone (175 ml) and concentrated hydrochloric acid (10.87 g) and the mixture was stirred for 10 minutes. Then, seed crystals (0.05 g) were added and the mixture was further stirred at 25-30° C. for 1 hour and, then, at -5° to -10° C. for another 1 hour. The resulting crystals were recovered by filtration, washed with methylene chloride and dried to give (±)-(2R*,4R*)-4-dimethylamino-2-phenyl-2-(2-pyridyl)valeramide hydrochloride (26.9 g).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:18]([CH3:29])[CH:17]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C1COCC1>[CH3:29][C:18]1[CH:17]=[C:16]([NH:15][C:8]2[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([CH:4]=[CH:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(C=CCN4CCOCC4)cc23)ccc1Oc1cccnc1
Temperature: 85 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1C(=O)CCC1.O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]-fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 mL) was added cyclopropylamine (6.9 mL, 99 mmol). The mixture was heated at 100° C. for 5 h. LC/MS analysis indicated ˜75% conversion to product, therefore a further portion of cyclopropylamine (2.3 mL, 33 mmol) was added, the mixture heated at 100° C. for 4 h and then cooled to ambient. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic portion was washed with sat. aq. NH4Cl (2×50 mL) and brine (50 mL) and then the aqueous portions re-extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4 and reduced in vacuo to give 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g).