Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:4][CH2:5]3)=[CH:13]1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (3-methylphenyl)acetic acid (31.4 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, light brown colored solid formed. The solid was filtered and dried to afford 7-methyl-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (57 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 3.16-3.23 (m, 2H), 3.72 (s, 3H), 3.82 (s, 2H), 4.17-4.24 (m, 2H), 7.06-7.14 (m, 3H), 7.20-7.27 (m, 3H), 7.30 (s, 1H), 8.11-8.18 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[C:7](/[CH:9]=[CH:19]/[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in THF (45.8 mL, 0.0458 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (7.8 mL, 0.0480 mol) in THF (58.4 mL). The reaction was warmed to RT and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (9.91 g, 0.0436 mol) in THF (11.7 mL). The reaction was allowed to warm up to RT and stirred at RT overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to provide the desired product (8.22 g, 75.3%). LCMS calculated for C14H22N2O2Na(M+Na)+: m/z=273.2; Found: 273.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(O)[CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Yield: 45.4 %

Procedure:
A mixture of ethyl 3,3-bis(4-fluorophenyl)-3-hydroxy-2-(1-methylethyl)propionate (0.35 g, 1 mmol) and p-toluene sulfonic acid (0.1 g) in 20 mL toluene was heated at reflux for 1.5 hours. The mixture was concentrated in vacuo and the residue dissolved in diethyl ether. The ether solution was washed with saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from cold petroleum ether to give 0.15 g of the title compound; m.p. =51.5°-52.5° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:42](B(O)O)([CH3:44])=[CH2:43]>C1COCC1.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([C:42]([CH3:44])=[CH2:43])[N:21]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B(O)O
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 25 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 18) (43 mg, 0.071 mmol) and isopropenyl boronic acid (Molander, G. A.; et. al. J. Am. Chem. Soc. 2003, 125, 11148-11149) (122 mg, 1.42 mmol) in THF (3 mL) and 1N aqueous potassium carbonate (3 mL). 1,1-Bis(di-t-Bu-phosphino)ferrocene palladium dichloride (4.6 mg, 0.0071 mmol) was heated at 80° C. for 4 h in a sealed tube. The mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=611.2; found=611.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.88 (s, 1H); 7.75 (s, 2H); 7.51 (s, 2H); 7.04 (br, s, 0.5H); 6.99 (br, s, 0.5H); 6.71 (s, 0.5H); 6.69 (s, 0.5H); 5.98 (s, 1H); 5.68 (br, s, 0.5H); 5.66 (br, s, 0.5H); 5.37 (m, 1H); 5.00-4.74 (m, 1H); 4.56-4.20 (m, 1H); 4.20-3.90 (m, 1H); 3.77 (s, 3H); 3.25-3.18 (m, 1H); 2.28 (s, 3H); 1.32-1.22 (m, 6H); 0.74 (br, s, 1.5H); 0.64 (br, s, 1.5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[CH:12]=[N:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=[CH:9][C:10]=23)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccc2c(-c3ccc(F)cc3)ncn12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c(-c3ccc(F)cc3)ncn12
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-fluorophenyl)-imidazo[1,5-a]pyridine-5-carboxylic acid ethyl ester (2.0 g, 7.0 mmol) in MeOH (233 mL) is added a solution of 85% KOH (4.6 g, 69 mmol) in H2O (35 mL) and the mixture is warmed at reflux. After 15 minutes, the reaction mixture is evaporated, diluted with water, and washed with EtOAc (2×200 mL). The aqueous layer is acidified with 1 N aqueous HCl (pH 5-6) to afford a precipitate. The solid is collected by filtration and triturated with 10% MeOH—CH2Cl2 to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[NH2:25].CS(O)(=O)=O.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CO>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH3:18])[N:5]=[CH:4][C:3]([C:19]#[N:20])=[C:2]2[NH:25][C:24]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:22]([Cl:21])[CH:23]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1N
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (11.64 g, 0.04 mol, 1.00 equiv), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (9.53 g, 0.04 mol, 1.00 equiv), methanesulfonic acid (1.3 ml, 0.02 mol, 0.5 equiv) in ethanol (30 ml) was stirred under refluxed for 6 hours and then 0.6N hydrogen chloride (600 ml, 0.36 mol) was added. The mixture was heated to 80° C. for additional 19 hours, and then cooled to 0° C. where the precipitated solids were formed and filtered. The product was added to a solution of 1N potassium carbonate (200 ml, 0.2 mol) in methanol (300 ml) and the resulting mixture was stirred for 3 hours. The resulting precipitated solids were filtered, washed with 1:1 methanol/water (500 ml) and dried to give 12.8 g of product. MS (ESI) m/z: 446 (M+1).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Na].[CH2:6]1[O:8][CH:7]1[CH2:9][CH2:10][CH:11]1[O:13][CH2:12]1>O>[CH2:1]([O:4][CH2:12][CH:11]1[O:13][CH:7]([CH2:6][OH:8])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C(CC1CO1)C1CO1
Reactant: C=CCO
Agent: [Na]
Solvent: O
Product: C=CCOCC1CCC(CO)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
100 ml of allyl alcohol (1.47 mole, Aldrich) is cooled to 5° in an ice-bath and under a nitrogen atmosphere 0.3 g of sodium (0.013 mole, washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred mixture. The addition of the sodium is made at such a rate that the temperature remains below 20°. After the addition of the sodium has been completed, the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, with stirring 15.0 g of 1,5-hexadiene diepoxide (0.131 mole) is added to the mixture. After the addition of the diepoxide has been completed, the reaction mixture is heated at reflux for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at 108°-110° @ 0.5 mm is collected yielding 14.65 g (65%) of the above compound.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[CH:9][N:8]=[C:7]1[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:5])=[O:4].C>C(OCC)(=O)C.[Pd]>[CH3:29][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH2:19])[CH:13]=2)=[CH:9][N:8]=[C:7]1[Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])(=[O:4])=[O:5]
Reactant: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1N
Reaction time: 14 h
Yield: 48.6 %

Procedure:
2-(tert-Butyl-dimethyl-silyl)-5-(4-methyl-3-nitro-benzyl)-imidazole-1-sulfonic acid dimethylamide (2.32 g) was dissolved in 125 ml of ethyl acetate and 0.50 g of 10% palladium over charcoal (Pd/C) was added. The reaction mixture was hydrogenated on a Parr shaker at 44 lb/in2 for 14 hr. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (1:3), giving 1.05 g of 5-(3-amino-4-methyl-benzyl)-2-(tert-butyl-dimethyl-silyl)-imidazole-1-sulfonic acid dimethylamide as a white solid. ##STR111##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (20:80).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](C)[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:5][CH:4]=1.C(N1C(=O)CC[C@@H]1C(OCC)=O)(OC(C)(C)C)=O.C(N1C(=O)CC[C@H]1C(OCC)=O)(OC(C)(C)C)=O>>[NH2:15][C@H:12]([CH2:13][NH2:14])[CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(C)CCC(N)CN)cc1
Agent: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Product: NC[C@@H](N)CCCc1ccc(O)cc1

Procedure:
This compound is prepared analogously to Intermediate K (NVP-QBM333), replacing Ethyl Boc-D-pyroglutamate in step 1 with Ethyl Boc-L-pyroglutamate; [M+H]+ 195
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[K+]>O.[Pd]>[CH3:10][CH:8]([CH2:7][C@H:6]([CH2:11][NH2:12])[CH2:5][C:4]([OH:15])=[O:3])[CH3:9]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
150 g of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; assay: 97.2%) were suspended in 300 mL of H2O. KOH (90.1.g, assay 86.1%, 2.05 eq.) was added. The initially turbid reaction mixture became clear which indicated that the reaction was nearly completed. After complete conversion (determined by HPLC) NH4-formate and Pd/C were added. The reaction mixture was stirred until complete conversion was observed. The solution was filtered and then concentrated to about 250 g under reduced pressure and 400 mL of 2-propanol were added. At a temperature of 45° C. acetic acid was added until a pH of 7.0 was reached. Pregabalin started to crystallize. Within about 60 minutes the reaction mixture was cooled down to 10° C. Stirring was continued for 1 hour, then the product was isolated by filtration. The filter cake was washed with 90 mL of a 1:1 mixture of cold H2O/2-propanol. After drying, 65 g of substantially pure pregabalin (purity 97.9%) were obtained (yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:17].N1C=CC=CC=1.[Br:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=O>C(OCC)(=O)C>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:26][C:25]([Br:24])([CH3:30])[CH3:29])=[C:3]([OH:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(Br)C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(Br)CNc1ccc(S(=O)(=O)c2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-benzenesulfonyl-phenol (1.06 g., 4.26 mmol) in 8 mL ethyl acetate was added pyridine (0.345 mL, 4.26 mmol). The solution was cooled to 0° C. and 2-bromo-2-methyl-propionyl chloride (0.553 mL, 4.47 mmol) was added dropwise and stirring was continuted for 2 hours. The reaction mixture was diluted with 50 mL ethyl acetate and washed with 50 mL 10% aqueous hydrogen chloride, 50 mL saturated aqueous sodium bicarbonate, 50 mL water, then 50 mL brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield 5-benzenesulfonyl-2-(2-bromo-2-methyl-propylamino)-phenol as a crude oil, which was used directly in the following step.
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[O:8])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]([CH2:18][CH3:19])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])=[O:8]
Reactant: CCC(C(=O)Nc1c(C)cccc1C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(N)C(=O)Nc1c(C)cccc1C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A mixture of 17.7 g (52.6 mmoles) of N-(2-phthalimido-butyryl)-2,6-dimethyl-aniline, 14.2 ml of a 85% aqueous hydrazine hydrate solution and 250 ml of ethanol is boiled for one hour, and then the mixture is processed as described in Example 11. The product is triturated with petroleum ether. 9.45 g of N-(2-amino-butyryl)-2,6-dimethyl-aniline are obtained; m.p.: 48°-49° C. The product is obtained with a yield of 87.1%. The hydrochloride of the compound melts at 213°-214° C. [the melting point reported in the literature (see E. W. Byrnes et al., loc. cit.) is 213.5°-214.5° C⟧
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])=[O:6])[CH:2]=[CH2:3].Cl.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCN=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCN=[N+]=[N-]
Reaction time: 6 h
Yield: 99.4 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-(t-butyldimethylsilyloxy) pyrrolidine (29.7 g) in tetrahydrofuran was added dropwise 12N hydrochloric acid (15 ml) at ambient temperature. After stirring for 6 hours, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with sat. sodium bicarbonate and brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R, 4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-hydroxypyrrolidine (20.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][C:3]=1[F:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:57][C:58]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([CH3:61])[CH2:59][OH:60].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:57][C:58]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([CH3:61])[CH2:59][OH:60])=[O:14])=[CH:11][C:10]=2[NH:18][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:4][C:3]=1[F:32]
Reactant: CC(N)(CO)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(N)c(F)c3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(CO)c4ccccc4)ccc3Sc3ccc(N)c(F)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To the product of Example 449F (150 mg, 0.31 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [HATU] (132 mg, 0.21 mmol) in DMSO (1.5 mL) was added the product of Example 449H (49 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) added dropwise at room temperature under N2. The mixture was stirred at room temperature for 2 hours, then poured into water (30 mL) with stirring. The resulting precipitate was extracted with ethyl acetate (1×30 mL). The organic layer was washed with water (3×15 mL) and 10% NaHCO3 (1×15 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography (SiO2, gradient elution of ethyl acetate/MeOH=98/2 to 95/5) to give a yellow solid. Trituration of product containing fractions with ethyl acetate gave the title compound as pale yellow crystal (86 mg, 48%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.69 (s, 3H), 3.23 (septet, J=7.0 Hz, 1H), 3.52 (dd, J=11.0, 6.3 Hz, 1H), 3.74 (dd, J=11.0, 5.9 Hz, 1H), 5.09 (dd, J=6.3, 5.9 Hz, 1H), 5.61 (s, 2H), 6.79 (dd, J=9.2, 8.4 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.99 (dd, J=8.4, 1.8 Hz, 1H), 7.08 (dd, J=11.4, 1.8 Hz, 1H), 7.17 (br-t, J=7.0 Hz, 1H), 7.27 (t, J=7.0 Hz, 2H), 7.33 (br-d, J=7.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.69 (dd, J=8.5, 1.8 Hz, 1H), 7.87 (d, J=1.8 Hz, 1H), 8.07 (s, 1H), 8.58 (s, 1H), 8.86 (d, J=8.4 Hz, 1H), 10.17 (s, 1H). MS ESI+ m/z: 583 (M+H), ESI− m/z: 581 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]1=[O:25].[CH2:26]([N:28]([CH2:39][CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH2:39][CH3:40])[CH2:26][CH3:27])=[CH:38][CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]1=[O:25]
Reactant: CCN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(CC)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 22.7 %

Procedure:
A mixture of 100 mg (0.25 mmol) of 3-(2,6-dichlorophenyl)-1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 120 mg (0.5 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 30 mg (22%) of 3-(2,6-dichlorophenyl)-1-ethyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an orange colored solid of melting point 85° C.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[N:30]1([C:37](OC2C=CC([N+]([O-])=O)=CC=2)=[O:38])[CH2:35][CH2:34][S:33](=[O:36])[CH2:32][CH2:31]1.O>CN1CCCC1=O.C(OCC)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][N:14]([C:37]([N:30]3[CH2:35][CH2:34][S:33](=[O:36])[CH2:32][CH2:31]3)=[O:38])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)F)cc2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCS(=O)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Reaction time: 0.12 h

Procedure:
2.2 g (7.7 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]piperidine-3-carboxylate were dissolved in 14 ml of N-methylpyrrolidone, and admixed with 4.0 ml (3.0 g, 23.0 mmol) of N,N-diisopropylethylamine and 3.3 g (11.5 mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate 1-oxide. The reaction mixture was converted in a microwave at 180° C. for seven minutes. Subsequently, water and ethyl acetate were added, and the aqueous phase was removed and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of preparative HPLC. Yield: 2.2 g (59% of theory)