Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:7]([C:6]3[C:2]([NH2:1])=[N:3][N:4]([C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([N:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])=[CH:38][CH:39]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: CN(C)c1ccc(-c2ccnc(-n3cc(C(=O)O)c(N)n3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(CCc2ccc(NC(=O)c3cn(-c4nccc(-c5ccc(N(C)C)cc5)n4)nc3N)cc2)CC1
Yield: 22.9 %

Procedure:
A mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (35 mg, 0.108 mM) diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (13 mg, 21% yield). ES-MS MH+526.7. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]=1[C:14]1[CH:18]=[CH:17][O:16][N:15]=1.C(N1CCC(Cl)=C(C2C[CH:37]([O:39][CH2:40]C)ON=2)C1)(=O)C1C=CC=CC=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]=1[C:14]1[CH:18]=[C:17]([CH2:37][O:39][CH3:40])[O:16][N:15]=1
Reactant: CCOC1CC(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)=NO1
Reactant: ClC1=C(c2ccon2)CNCC1
Agent: O=C(O)C(=O)O
Product: COCc1cc(C2=C(Cl)CCNC2)no1

Procedure:
4-Chloro-3-(3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate starting from 1-benzoyl-4-chloro-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. M.p. 195°-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:27])[C:18]2=[O:28])[CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:41]([NH:43][NH2:44])=[O:42]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:27])[C:18]2=[O:28])[CH2:13][C:14]2[O:16][CH:41]=[N:43][N:44]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:41](=[N:43][NH:44][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:27])[C:18]1=[O:28])=[O:42]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(C)c3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3cccc(C)c3C2=O)ccc1OC
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3cccc(C)c3C2=O)ccc1OC
Yield: 54.1 %

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-4-methylisoindoline-1,3-dione was prepared by the procedure of Example 1. Reaction of 3-(3-ethoxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (2.03 g, 5.29 mmol), carbonyldiimidazole (1.03 g, 6.35 mmol) and formic hydrazide (420 mg, 6.99 mmol) in tetrahydrofuran (20 mL) gave crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanamide(610 mg, 1.43 mmol), which was then treated with phosphorus oxychloride (0.4 mL, 4.3 mmol) in acetonitrile (6 mL). The product was obtained as a white solid (311 mg, 14% overall yield): mp, 96.0-98.0° C.; 1H NMR (CDCl3) δ 1.47 (t, J=6.9 Hz, 3H, CH3), 2.67 (s, 3H, CH3), 3.81 (dd, J=6.0, 15.7 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.12 (q, J=6.9 Hz, 2H, CH2), 4.37 (dd, J=10.2, 15.6 Hz, 1H, CHH), 5.81 (t, J=6.0, 10.3 Hz, 1H, NCH), 6.83 (d, J=8.7 Hz, 1H, Ar), 7.14-7.17 (m, 2H, Ar), 7.43 (d, J=7.6 Hz, 1H, Ar), 7.54 (t, J=7.3 H, Ar), 7.63 (d, J=7.1 Hz, 1H, Ar), 8.30 (s, 1H, CH); 13C NMR (CDCl3) δ 14.69, 17.52, 27.71, 51.62, 55.92, 64.46, 111.37, 112.63, 120.33, 121.06, 128.31, 130.33, 132.07, 133.59, 136.55, 138.18, 148.39, 149.42, 153.02, 164.08, 168.04, 168.53; Anal Calcd for C22H21N3O5+0.2 H2O: C, 64.29; H, 5.25; N, 10.22; H2O, 0.90. Found: C, 64.62; H, 5.30; N, 9.83; H2O, 0.71.
Reaction SMILES: [CH3:1][Si:2]([N-:5][Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[Li+].Cl[C@@H:12]([B:17]1[O:21][C@@H:20]2[CH2:22][C@@H:23]3[CH2:26][C@H:25]([C@:19]2([CH3:29])[O:18]1)[C:24]3([CH3:28])[CH3:27])[CH2:13][CH:14]([CH3:16])[CH3:15]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[N:5]([C@H:12]([B:17]1[O:21][C@@H:20]2[CH2:22][C@@H:23]3[CH2:26][C@H:25]([C@:19]2([CH3:29])[O:18]1)[C:24]3([CH3:27])[CH3:28])[CH2:13][CH:14]([CH3:16])[CH3:15])[Si:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)C[C@@H](Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1)N([Si](C)(C)C)[Si](C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (189 ml, 0.189 mol) was added, over 30 minutes, to a solution of crude 2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole of Step 2 (59.0 g, 91% purity, 0.189 mol) in tetrahydrofuran (580 ml) while cooling at −78° C. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed by rotary evaporation and the residue taken up with dry hexane (800 ml). The resulting suspension was stirred at room temperature for 2 hours, then the solid was removed by filtration on a celite cake, which was washed with dry hexane (3×100 ml). The filtrate was concentrated giving a satisfactorily pure product as a brown oil (79 g) in practically quantitative yield. The product was used for the subsequent step without further purification.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.OO.C([OH:22])C>O.CO>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:22])[C:11]([CH3:17])=[N:10]1
Reactant: Cc1nn(C2CCCC2C)c(N)c1C#N
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Temperature: 25 °C
Yield: 84 %

Procedure:
85% Potassium hydroxide (5.8 g, 88.5 mmol) was dissolved in water (50 ml) and the solution was cooled in an ice bath for 1 hour. The 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.6 g, 12.7 mmol) in methanol (5.0 ml)/water (25 ml) was then added, followed by 30% hydrogen peroxide (6.5 ml, 63.2 mmol). The reaction mixture was stirred with ice-bath cooling for 4 hours, then was warmed slowly to room temperature. Ethanol was added to the reaction mixture to completely dissolve the starting material and the mixture was stirred at room temperature for 60 hours. The ethanol was removed in vacuo and the oily residue was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous MgSO4 and the solvents were removed in vacuo to afford an amber solid. Recrystallization from acetonitrile and air drying then afforded 2.4 g (84%) of 1-(2-methylcyclopentyl)-3-methyl-5-amino- 1H-pyrazole-4-carboxamide as an off-white solid, m.p. 124°-126° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH2:22]C)=[CH:19][CH:18]=[C:17](C[N+]([O-])=O)[C:10]=1[CH:11]=[CH:12][CH2:13][N+]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=C(C[N+]([O-])=O)C=1C=CC[N+:41]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:10]=1[CH:11]=[C:12]([CH3:13])[NH:41]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Reactant: COc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Product: COc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Yield: 40 %

Procedure:
This compound is obtained according to the operating method described in Example 2b, in which the 2-benzyloxy-3-ethoxy-6,β-dinitromethylstyrene is replaced with 2-benzyloxy-3-methoxy-6,β-dinitromethylstyrene. A pale yellow powder (yield=40%, m.p.=74°-75° C.) is obtained.
Reaction SMILES: [C:1]([C:3]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[C:10]([F:21])[CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[N:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)=[C:23]=[S:24].C[OH:38].Cl>CN(C=O)C.O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:22]2[C:1](=[O:38])[C:3]3([CH2:6][CH2:5][CH2:4]3)[N:7]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[C:10]([F:21])[CH:9]=3)[C:23]2=[S:24])=[CH:26][C:27]=1[C:33]([F:34])([F:36])[F:35])#[N:30]
Reactant: CNC(=O)CCCc1ccc(NC2(C#N)CCC2)cc1F
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 80 °C
Yield: 62 %

Procedure:
A mixture of 4-(4-(1-Cyanocyclobutylamino)-2-fluorophenyl)-N-methylbutanamide (79) (7 mg, 0.02 mmol) and 4-isothiocyanato-2-trifluoromethylbenzonitrile (96) (12 mg, 0.05 mmol) in DMF (1 mL) was heated to 80° C. using microwave for 16 h. To this mixture was added methanol (3 mL) and aq. 1 N HCl (3 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)-2-fluorophenyl)-N-methylbutanamide (78) [ND-7] (8 mg, 62%) as a pale yellowish solid: 1H NMR δ 7.98 (d, 1H, J=8.2 Hz) 7.97 (d, 1H, J=2.0 Hz) 7.84 (dd, 1H, J=8.2, 2.0 Hz), 7.43 (dd, 1H, J=8.0, 8.0 Hz), 7.06 (dd, 1H, J=8.0, 2.0 Hz), 7.02 (dd, 1H, J=9.7, 2.0 Hz), 2.83 (d, 3H, J=4.8 Hz) 2.78 (t, 2H, J=7.7 Hz) 2.63-2.71 (m, 2H), 2.51-2.62 (m, 2H), 2.27 (t, 2H, J=7.3 Hz) 2.18-2.27 (m, 1H), 2.00-2.09 (m, 2H), 1.66-1.76 (m, 1H); 13C NMR δ 179.9, 174.7, 172.8, 161.2 (d, J=247 Hz), 137.0, 135.2, 134.1 (d, J=9.6 Hz), 133.6 (q, J=33.7 Hz), 132.1, 131.9 (d, J=5.6 Hz), 130.8 (d, J=15.2 Hz), 127.1, 125.7 (d, J=3.9 Hz), 121.9 (q, J=272 Hz), 117.3 (d, J=22.3 Hz), 114.8, 110.0, 67.4, 35.8, 31.5, 28.3, 26.4, 25.6, 13.7.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22]([Cl:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC1C=CC=CC=1>[ClH:30].[C:22]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reaction time: 3 h
Yield: 54 %

Procedure:
To a stirred mixture of 19 parts of 1-(phenylmethyl)-4-piperidinol, 15.2 parts of N,N-diethylethanamine and 180 parts of methylbenzene were added dropwise (slowly) 14 parts of benzoyl chloride. Upon completion, stirring was continued for 3 hours at room temperature. The formed hydrochloride salt of benzoyl chloride was filtered off and washed with methylbenzene. The filtrate was evaporated. The oily residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 18 parts (54%) of [1-(phenylmethyl)-4-piperidinyl] benzoate hydrochloride; mp. 225.9° C. (intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[C:4]([NH:10][C@H:11]([C@@H:34]([OH:36])[CH3:35])[C:12]([NH:14][NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:48]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])([CH3:50])[CH3:49]>CCOC(C)=O.O>[Si:52]([O:36][C@@H:34]([CH3:35])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:37])[C:12]([NH:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:13])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:54])[CH3:53]
Reactant: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 107.3 %

Procedure:
A 100 mL round bottomed flask was charged with N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(4-methoxybenzyloxy)benzohydrazide (3.53 g, 6.7 mmol) and DMF (120 mL). Imidazole (1.84 g, 27 mmol) and tert-butyldimethyl silyl chloride (2.52 g, 16.75 mmol) were then added to the mixture which was stirred at room temperature for 17.5 h. Water (60 mL) was added to the mixture followed by EtOAc (100 mL). The phases were partitioned and the organic phase washed with water (70 mL) (×4), brine (50 mL), dried (Na2SO4) and concentrated to furnish a white solid. Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a colorless oil (4.58 g, 35% yield). No 1H data available.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[OH:15])=[O:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCCC2(CCCC2)C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC2(CCCC2)C1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.1 g) obtained in Step 3 and triethylamine (19.9 mL) in chloroform (100 mL) was added dropwise methanesulfonyl chloride (5.2 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 2 hours. Then, after addition of triethylamine (10 mL), the reaction mixture was stirred at room temperature for 30 minutes. After ice-cooling, ice-cold water (30 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added to the reaction mixture, followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated to give a crude 6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22](Cl)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C1CCN(CC2COCCN2)C1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCOCC1CN1CCCC1
Yield: 53.1 %

Procedure:
The procedure described in Example 17 was repeated, but using 1.64 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 3.72 ml of triethylamine and 1.54 g of 3,4-dichlorophenylacetyl chloride, to afford 0.72 g of the title compound, melting at 268° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:4]([CH2:33][CH:32]=[CH2:31])[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: C=CCBr
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1C(OC)=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (4.0 g, 12.0 mmol; see Example 1A) in dry dimethylformamide (10 ml) was treated with finely ground potassium carbonate (6.6 g, 48.0 mmoles) and allyl bromide (1.7 ml, 20.0 mmole). The resulting suspension was allowed to stir under argon at room temperature for 10 hours. The reaction was diluted with ethyl acetate, filtered and the filtrate was washed with water and brine. It was dried over anhydrous magnesium sulfate and evaporated to provide a yellow oil. Purification by flash chromatography (20% ethyl acetate in hexanes) yielded the title compound (2.64 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:3]=1.S1(C[CH2:29][CH2:28][CH2:27]1)(=O)=O.C([Br:34])C=C>CCOCC>[Br-:34].[CH2:29]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N+:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:28]=[CH2:27]
Reactant: CCCCCCCCCCCCCCCCn1nc(C)cc1C
Reactant: O=S1(=O)CCCC1
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CCn1c(C)cc(C)[n+]1CCCCCCCCCCCCCCCC
Product: [Br-]
Reaction time: 24 h

Procedure:
A mixture of 50 g (0.156 mol) of 3,5-dimethyl-1-hexadecylpyrazole, 200 ml of sulfolane and 19 g (0.156 mol) of allyl bromide is stirred and kept at a temperature of 80° C. for 24 hrs. The reaction mixture is allowed to cool and 100 ml of ether are added. The mixture is stirred for another 2 hrs and the crystalate is then filtered off, washed with ether, and vacuum dired at 40° C./12 Torr. Recrystallization from 200 ml of ethyl acetate yields 39.6 g of 2-allyl-3,5-dimethyl-1-hexadecyl-pyrazolium bromide; m.p. 99°-100° C.
Reaction SMILES: C[N:2]1CCOCC1.[N+:8]([C:11]1[N:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9].ClC(OCC(C)C)=O.Cl.[F:29][C:30](N)([F:34])[C:31]([F:33])=[CH2:32]>C1COCC1>[N+:8]([C:11]1[N:12]([CH2:16][C:17]([NH:2][CH2:32][C:31]([F:33])=[C:30]([F:34])[F:29])=[O:19])[CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9]
Reactant: CN1CCOCC1
Reactant: O=C(O)Cn1ccnc1[N+](=O)[O-]
Reactant: C=C(F)C(N)(F)F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cn1ccnc1[N+](=O)[O-])NCC(F)=C(F)F
Reaction time: 0.17 h

Procedure:
N-methylmorpholine (1.01 g, 10 mmol) was added to 2-(2-nitro-1H-imidazol-1-yl)acetic acid (1.71 g, 10 mmol) in 150 mL of dry THF under nitrogen at 0° C. and stirred for 10 minutes. Isobutyl chloroformate (1.43 mL, 11 mmol) was added. After 30 minutes, 1,1,2-Trifluoro allyl amine hydrochloride (1.62 g, 11 mmol) and N-methylmorpholine (1,21 g, 12 mmol) was added to the solution and the mixture stirred at room temperature overnight. The solution was then filtered and the organic solvent evaporated to give a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH3:11][Mg]Br.Cl>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1)[CH3:11]
Reactant: C[Mg]Br
Reactant: Cc1ccc(C=O)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(C)O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36 mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47 mL) of methylmagnesium bromide (0.44 mmol) in THF. The temperature of the reaction mixture was allowed to rise back to room temperature, at which the reaction mixture was stirred for 1 hour. Then, 2 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield title compound as a pale yellow oil (55.8 mg, quantitative).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.O[CH:13]([C:16]1[NH:17][CH:18]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:22])[CH:21]=1)OC.[C:31]([CH:36]=[P:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([O:33][CH2:34][CH3:35])=[O:32]>O1CCOCC1>[O:22]=[C:20]1[C:19]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][NH:17][C:16]([CH:13]=[CH:36][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21]1.[C:50]1([P:37](=[O:8])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
0.5 g of p-toluenesulfonic acid, 6.26 g of 2-(1-hydroxy-1-methoxymethyl)-5-(phenylmethoxy)-4(1H)-pyridinone and 8.35 g of carbethoxymethylenetriphenylphosphorane were stirred for 3 hours in 100 ml of dioxane at 70° C. A clear, dark-colored solution was formed. Evaporation of the solvent in vacuo yielded an oily residue of the title compound and triphenylphosphine oxide. The residue was dissolved in 30 ml of isopropanol and crystals of product began to separate. After standing in a refrigerator overnight, the crystals were filtered off, washed with ether and recrystallized from isopropanol. Yield: 5.72 g, melting point 188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[N:10]([O-])=O.[Na+].Cl.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])=O.[Na+]>CCO.O.CCO>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([N:1]=[N:10][C:18]2[CH:19]=[CH:20][C:15]([OH:21])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=N[O-]
Reactant: Nc1ccc(CO)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(N=Nc2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Aminobenzyl alcohol (0.36 g, 2.92 mmol) and NaNO2 (0.22 g, 3.21 mmol) were dissolved in 7.5 mL EtOH:water (1.5:1), added to 2 N HCl solution (4.5 mL) and stirred at 0° C. for 1 hour. Phenol (0.275 g, 2.92 mmol) in EtOH was added followed by NaOAc (0.15 g) at 0° C. and stirred for 6 hours at room temperature. Reaction mixture was quenched with saturated sodium bicarbonate solution (150 mL) and extracted with DCM. The organic layer was washed with water (200 mL), brine (950 mL), and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc:n-hexane 4:6) to obtain compound 1. Yield: 0.473 g (71%). 1H NMR and mass-spectrum data are in good agreement with previously published results.27