Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].O.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([S:27][C:28]#[N:29])[CH:24]=[CH:23][C:21]=2[N:22]=1>O1CCCC1>[S:27]([C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[S:19][C:20]=2[CH:26]=1)[C:28]#[N:29]
Reactant: N#CSc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen carbonate and 9.4 cm3 of water are added, at 20° C., to a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran. The resulting mixture is subsequently stirred at 20° C. for 20 h and then extracted with 2×150 cm3 of ethyl acetate. The organic phases are combined and then washed with 3×50 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and the product is spin-filter-dried and dried under vacuum at 20° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=[C:12]([F:11])[CH:13]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-fluoro-5-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 263-265° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(3-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.045 g, 0.11 mmol) and ammonium acetate (0.0842 g, 1.09 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.27 mL, 0.27 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#N)C.C(=O)([O-])[O-].[K+].[K+].CI>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:23])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: Cc1c(OCc2ccccc2)c(=O)c(C(O)C(F)(F)F)cn1C
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (2.07 g, 6.6 mmol), acetonitrile (60 mL), potassium carbonate (2.62 g. 19 mmole) and methyl iodide (15 mL, 0.24 mol) was heated to reflux for 30 min. On cooling to RT, the reaction mixture was filtered over a pad of CELITE™, and the filtrate was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane, and the resulting solution was washed with brine, dried over Na2S04, filtered and concentrated to afford 3-benzyloxy-1,2-dimethyl5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.48 g, 70% yield, HPLC Method 1 (Example 24), RT=15.4 min, HPLC purity (peak percent area): 99.9% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.75 (s, 1H), 7.37, (m, 5H), 5.35 (q, J=7.1 Hz, 1H), 5.01 (m, 2H), 3.63 (s, 3H), 2.18 (s, 3H); MS-ESI (m/z) 328.1 [M+1]+, 220.2, 91.2 (100%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][C:20]([CH3:30])([CH2:27][CH2:28][CH3:29])[CH2:21][C:22](OCC)=[O:23]>C1COCC1.O.C(O)(=O)C>[CH3:19][C:20]([CH3:30])([CH2:27][CH2:28][CH3:29])[CH2:21][C:22](=[O:23])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCC(C)(C)CC(=O)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCC(C)(C)CC(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
Dimethyl methylphosphonate (11.7 g, 102 mmol) was dissolved in anhydrous THF (200 ml) and the resulting solution was cooled to -78° C. under argon atmosphere. A solution of n-butyl lithium in hexane (1.63N, 62.3 ml, 102 mmol) was added and the mixture was stirred for 30 minutes. A solution of ethyl 3,3-dimethylhexanoate (7.00 g, 40.6 mmol) in anhydrous THF (50 ml) was added to the reaction mixture at -78° C. andthe mixture was stirred for 30 minutes and then at room temperature for further 2 hours. Acetic acid was added to neutralize the solution. Water (20 ml) was added and then the solution was concentrated. The resulting residue were partitioned between ethyl acetate (200 ml) and water (10 ml). The ethyl acetate layer was separated, washed with water (80 ml) and with brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to give oily product, dimethyl 4,4-dimethyl-2-oxoheptylphosphonate (8.11 g, 32.4 mmol, 79.8%, b.p.: 101°-104° C./0.03 mmHg). The structure was identified by the following data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure IIa. Obtained as a light brown solid (1.84 g, 95%). MS (ISP) 486.9 [(M+H)+]; mp 179° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][N:22]2[C:21](=[O:23])[C:20]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]3[C:18]2=[O:28])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)ON=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To 140 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-(tert-butyl)oxime in 2 ml of N,N-dimethylformamide, 91 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 162 mg of the desired product as a colorless resinous substance.
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][O:22]CC2C=CC=CC=2)=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][OH:22])=[CH:17][CH:18]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(CO)Nc1ccc(NC(=O)CO)cc1
Reaction time: 5 h

Procedure:
2-Benzyloxy-N-[4-(2-benzyloxy-acetylamino)-phenyl]-acetamide 3 (10 grams, 24.75 mmol) is dissolved in methanol (100 mL) in a pressure vessel. Pd/C (10%, 3 grams) is added, and the mixture is stirred under an atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed by filtration, and the methanol is distilled off. The crude 4 can be purified in a suitable solvent.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>[Pd].C(#N)C>[NH2:12][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC#N
Product: COC(=O)c1cccc(C)c1N
Temperature: 70 °C
Reaction time: 8.5 h
Yield: 96.6 %

Procedure:
Methyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5% Pd/C (Degussa CE 105 XRC/W, 1.0 g), and acetonitrile (300 mL) were combined in a 600-mL pressure vessel. The mixture was heated to 70° C. and hydrogenated at 65 psi (450 kPa) for 8 h. More 5% Pd/C (1.0 g) was added and hydrogenation was continued at 100 psi (690 kPa) for 8.5 h. Then the reaction mixture was cooled, purged with nitrogen, and filtered through Celite® diatomaceous filter aid, rinsing with acetonitrile (3×25 mL). The combined filtrates were partly evaporated to a weight of ˜160 g, and then diluted with acetonitrile to a total weight of 200g. Quantitative HPLC of this solution showed 40.3 wt % of the title compound (80.6 g, 97.5% yield).
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[NH4+:6].[NH4+].[NH4+].[Cl-:9].[Na+:10]>O>[P:1]([OH:5])([O-:4])([O-:3])=[O:2].[NH4+:6].[Na+:10].[Cl-:9].[NH4+:6].[P:1]([OH:5])([O-:4])([O-:3])=[O:2].[NH4+:6].[NH4+:6]
Reactant: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])O

Procedure:
Sodium ammonium phosphate and ammonium chloride are prepared from an ammonium phosphate (e.g., diammonium phosphate) and sodium chloride in water. The crystallization of sodium ammonium phosphate may take place between -10° C. to 40° C. Using the present invention, technical grade sodium ammonium phosphate and ammonium chloride can be produced from fertilizer grade diammonium phosphate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19]([CH3:25])[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1[nH]cnc1CN1CCc2c(C)c3ccccc3n2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C)c1C)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (343 mg) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in mineral oil, 51.3 mg) at 5° C. and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (182 mg) in N,N-dimethylformamide (10 ml) was added dropwise to the solution at 50° C. during 2 hours. After 30 minutes of stirring at the same temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with a mixture of tetrahydrofuran and ethyl acetate (1:3, 20 ml), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (3% -methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[(1,5-dimethylimidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one as crystal. The crystal was dissolved with 2N-hydrochloric acid (2 ml) and evaporated in vacuo. The crystalline residue was washed with acetone to give 3,4-dihydro-5-methyl-2-[(1,5-dimethylimidazol-4-yl)methyl]pyrimido[1,6-a]indol-1-(2H)one hydrochloride (0.2 g).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(Cn2ccnc2C=Cc2ccc([N+](=O)[O-])o2)cc1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 2-[2-(5-nitro-2-furyl)vinyl]imidazole and 4-methoxybenzyl bromide. Recrystallization from benzene-ethanol gave an orange solid, mp 151°-152°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.NCC1CN(C(O[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)CC=1.C(=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>CO>[CH2:29]([NH:1][CH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCC1=CCN(C(=O)OCc2ccccc2)C1
Reactant: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=Cc1ccccc1
Product: O=C(OCc1ccccc1)N1C[C@H](CNCc2ccccc2)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture (310 mg) of (3S,4R)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-aminomethyl-1-benzyloxycarbonyl-3-pyrroline was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (130 mg) and then benzaldehyde (0.13 mL) were added and the mixture was stirred at room temperature for 1 hour. Subsequently, a borane/pyridine complex (0.19 mL) was added and the reaction mixture was further stirred at room temperature for 4 hours. 6 mol/L hydrochloric acid (2 mL) was then added and the mixture was stirred at room temperature for 1 hour, followed by addition of a 30% aqueous solution of sodium hydroxide to make the mixture basic. The mixture was then extracted with diethyl ether (3×10 mL) The diethyl ether layers were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give (3S,4R)-3-benzylaminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale yellow oil (177 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:27][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]3[CH:8]=[CH:7][S:27][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Product: c1ncn(-c2nc(NCCc3ccc4c(c3)OCO4)c3ccsc3n2)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:11]1[C:19]2[N:18]=[CH:17][N:16]([CH3:20])[C:15]=2[C:14](SC)=[N:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[CH2:4]([N:11]1[C:19]2[N:18]=[CH:17][N:16]([CH3:20])[C:15]=2[C:14]([NH:2][NH2:3])=[N:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CSc1nc(=O)n(Cc2ccccc2)c2ncn(C)c12
Reactant: NN
Solvent: O
Product: Cn1cnc2c1c(NN)nc(=O)n2Cc1ccccc1
Temperature: 25 °C

Procedure:
After 16.0 ml of hydrazine hydrate was added to 2.00 g (6.99 mmol) of Compound h prepared in Reference Example 8, the mixture was stirred at room temperature for day and night. The reaction mixture was poured onto 300 ml of water and the precipitates were taken out by filtration and washed with ether to give 1.60 g (yield, 85%) of Compound p as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](=O)[CH3:13])[C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.O>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:12]([CH3:13])=[CH:11]2
Reactant: CC(=O)Cc1cccc(F)c1C(=O)O
Reactant: Nc1cccnc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2cccc(F)c2c(=O)n1-c1cccnc1
Yield: 16.3 %

Procedure:
2-Fluoro-6-(2-oxo-propyl)-benzoic acid (12.33 g, 31.43 mmol) and 3-aminopyridine (5.12 g, 54.4 mmol) in 25 mL dioxane were refluxed overnight. The reaction mixture was poured into water (250 mL). The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over MgSO4 and filtered through a pad of silica gel. The silica gel pad was washed with 250 mL ethyl acetate. The organic fractions were combined and rotavaped. The crude product was flash chromatographed on silica gel (eluent: 50% heptane/ethyl acetate to ethyl acetate) to obtain the product as a pale pink solid (1.3 g, yield 16.3%). LC-MS (m/z) 255.5 (MH+); tR=0.64. 1H NMR (500 MHz, CDCl3): 1.99 (s, 3H, Me), 6.43 (s, 1H), 7.07 (dd, J=8.12 Hz, J=11.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.49 (dd, J=4.9 Hz, J=8.1 Hz, 1H), 7.58 (td, J(d)=4.8 Hz, J(t)=8 Hz, 1H), 7.64 (unresolved dt, J(d)=8.1 Hz, J(t)=ca. 1.5 Hz, 1H), 8.53 (d, J=2 Hz, 1H), 8.71 (d, J=4.8 Hz, J=0.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[N:18]([CH3:29])[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:21]=2)=[CH:11][C:10]=1[CH3:30])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38](I)[CH3:39]>>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:17]2[N:18]([CH3:29])[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:38][CH3:39])=[CH:11][C:10]=1[CH3:30])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2cc(-c3ccc(Cl)cc3)nn2C)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(CC)c2cc(-c3ccc(Cl)cc3)nn2C)cc1C
Temperature: 95 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of example 15 (1.8 g, 4 mmol) in MIK (50 mL) was treated with Cs2CO3 (5 g, excess) and Ethyl iodide (2 mL). The resulting mixture was stirred at 95° C. overnight under pressure. After cooling to rt the reaction mixture was filtered off and the filtrate was evaporated off. The residue was diluted with DCM, washed with water and drying over Na2SO4 and filtration evaporation to give the title compound (320 mg, 0.68 mmol) as oil in a 17% yield after purification by flash chromatography.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(OCC)(=O)C>[Cl:17][S:18]([NH:21][C:22]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:23])(=[O:20])=[O:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Cl)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 13.8 g of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to form a solution of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0° C., at which temperature a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)2-pyridinecarboxamide (prepared from a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide in 500 ml of ethyl acetate by the addition of 46.4 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.25 mol) and stirring for 30 minutes) was added slowly. Then 150 ml of dichloromethane was added, and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mol), followed by 300 g of ice and 200 ml of water. The pH was 6.5. After stirring for 11/2hours, the two phases were separated and the aqueous phase was washed with three 200 ml portions of ethyl acetate. After removal of residual ethyl acetate in vacuo, the pH of the aqueous phase was adjusted to 2 by the slow addition of 2N hydrochloric acid (47 ml) with cooling. The crystals were filtered off, suspended in 200 ml of ethyl acetate and stirred for one hour. Then the crystals were filtered off, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried in vacuo, to yield 28.6 g of the title compound, melting point 190°-200° C., dec.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][C:14]([Cl:3])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
30.93 g of thionyl chloride are added dropwise to a warmed, mechanically stirred mixture of 45.12 g of 2,6-dichlorophenylacetic acid in 125 ml of toluene. The reaction mixture is then maintained at reflux for 5 hrs and cooled overnight at RT. The reaction mixture is concentrated in vacuo and the concentrate dissolved in hot petroleum ether and the solids filtered. The filtrate is concentrated in vacuo to give a dark amber liquid, which is distilled to give a clear pinkish liquid.