Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]2([O:10][CH2:9]2)[CH2:7][CH2:6]1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.C(OCC)(=O)C.CN(C)C=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH2:9][C:8]2([OH:10])[CH2:11][CH2:12][N:5]([CH2:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[F:1])[CH2:6][CH2:7]2)[CH:23]=1
Reactant: Fc1ccccc1CN1CCC2(CC1)CO2
Reactant: Oc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1ccc(Br)cn1CC1(O)CCN(Cc2ccccc2F)CC1
Yield: 37.1 %

Procedure:
7.00 g (0.0316 mol) of N-(2-fluorobenzyl)-1-oxa-6-azaspiro[2,5]-octane and 5.50 g (0.0314 mol) of 5-bromo-2-hydroxy-pyridine were weighed and added into 40 mL of N,N-dimethylformamide, and then 0.53 g (0.004 mol) of potassium carbonate was added. The reaction was stirred and reacted at a bath temperature of about 80° C. for 1 day and the solvent was recovered under reduced pressure. Potassium carbonate aqueous solution was added to the residue and the mixture was extracted with dichloromethane twice, combined, washed with water and dried, and the solvent was recovered. The residue was crystallized with petroleum ether-ethyl acetate to obtain a colorless flake-like crystal, 4.20 g, yield 69.3%. 1H-NMR (CDCl3, ppm) δ: 7.413 (1H, s), 7.399 (1H, dd, J1=8.20 Hz, J2=2.80 Hz), 7.358 (1H, t×d, J1=7.28 Hz, J2=1.68 Hz), 7.229 (1H, m), 7.096 (1H, t×d, J1=7.56 Hz, J2=1.12 Hz), 7.021 (1H, hept→t, J1=9.80 Hz), 6.543 (1H, dd, J=8.12 Hz), 3.994 (2H, s), 3.848 (1H, s), 3.602 (2H, s), 2.699 (2H, dd, J1=7.56 Hz, J2=3.82 Hz), 2.46 (2H, t×d, J1=8.96 Hz, J2=2.52 Hz), 1.54-1.74 (4H, m). The product was heated and dissolved in ethanol-ethyl acetate, salified with HCl-EtOH while warm and naturally cooled to obtain a colorless fine granular crystal, which was dried under vacuum to obtain 4.60 g product. Melting point: 184-186° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=[C:2]([NH:30][CH:28]2[CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:29]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(Cl)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(NC2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 75 °C
Yield: 86.2 %

Procedure:
A solution of 2-{4,6-dichloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-5-yl}ethanol (as prepared in Preparation 2)(0.652 g, 2.23 mmol) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.9 mmol) in DMSO (10.0 mL) was treated with DIPEA (0.7 mL, 4 mmol) and heated at 75° C. for 5 days in a sealed tube. The mixture was poured into a flask containing water and the resulting solids were collected by filtration and rinsed with water. The solids were taken up in DCM, dried over MgSO4 and filtered. The filtrate was purified directly by silica gel chromatography using a gradient of 25-100% EtOAc/heptane as eluent to give 0.823 g (86%) of the title compound as a crisp foam. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=5.6 Hz, 1 H), 4.71 (t, J=5.2 Hz, 1 H), 4.62-4.53 (m, 1 H), 4.47-4.40 (m, 1 H), 4.13-4.04 (m, 3 H), 3.89-3.78 (m, 3 H), 3.66 (d, J=11.4 Hz, 1 H), 3.55-3.44 (m, 3 H), 3.36 (dt, J=11.7, 2.9 Hz, 1 H), 3.04 (dt, J=12.9, 3.7 Hz, 1 H), 2.69 (t, J=6.9 Hz, 2 H), 1.39 (s, 9 H), 1.14 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(Cl)cc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(Cl)cc1
Yield: 42.9 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 250 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 1.193 g of 4-chloroaniline in place of the 2-fluoroaniline. 140 mg of N-(4-chlorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:30])[N:14]([CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15]2)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:23]([O:22][CH2:21][CH2:20][N:14]1[CH2:15][CH:16]2[NH:11][CH:12]([CH2:19][CH2:18][CH2:17]2)[C:13]1=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: O=C1C2CCCC(CN1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1C2CCCC(CN1CCOCc1ccccc1)N2
Yield: 91.1 %

Procedure:
3-(2-Benzyloxyethyl)-2-oxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 5, 0.15 g, 0.36 mmol) was dissolved in MeOH (5 mL), and palladium (10%) on activated carbon (0.03 g) was added. Hydrogen was applied via balloon for 1 hour. The black suspension was then filtered through compacted Celite, and the methanol was removed by high-vacuum rotary evaporator to give Compound 6 (0.09 g, 90%) as a thick oil, which was of sufficiently good quality to be advanced to the coupling reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([Cl:35])[CH:34]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:53].OS(C(F)(F)F)(=O)=O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:35][C:33]1[CH:34]=[C:29]([CH:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:53])[CH:4]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=2)([CH3:15])[CH3:16])[CH3:11])[CH:30]=[N:31][CH:32]=1
Reactant: [IH2+]
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)cc1)c1cncc(Cl)c1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)c(I)c1)c1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
The procedure of Barluenga (J Org Chem 1990, 55, 3104) was used. Thus, to a solution of N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Example 398, 22 mg, 0.041 mmol) and bis(pyridine)iodonium tetrafluoroborate (30 mg, 0.082 mmol) in 0.3 mL anhydrous CH2Cl2 was added triflic acid (18 μL, 0.20 mmol). After stirring at room temperature for 50 min, the reaction mixture was poured into a mixture of ice (20 g) and sodium bisulfite (1 g) and was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by preparative HPLC eluting on a reverse-phase HPLC column with 75 to 100% water in acetonitrile (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.82 (m, 1H), 7.36 d, 1H), 7.22 (d, 1H), 7.08 (d, 1H), 6.78 (dd, 1H), 4.29 (m, 1H), 3.03 (dd, 1H), 2.94 (m, 1H), 2.64 (dd, 1H), 1.78 (s, 3H), 1.75 (s, 3H), 0.88 (d, 3H). LC-MS: m/e 652 (M+H)+ (4.1 min).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[N:16](C3CCCCO3)[N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].Cl.O.[OH-].[Na+]>CCO>[N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of 2-nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile (17.7 g, 59 mmol) in EtOH (440 ml) was added 44 ml of concentrated HCl. The reaction mixture was stirred at RT for 1.5 h. The mixture was poured into water (1 l), and 2 M NaOH-solution was added until pH was 12. Thus resulting precipitate was filtered, washed with water and dried to give 11.7 g (92%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.09 (d, 1H), 7.91 (d, 1H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.73 (d, 1H), 13.4 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[C:37]4[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]5[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=5[O:52][CH3:53])[C:36]=4[CH:35]=[CH:34]3)[CH2:24]2)[CH3:21])[CH2:17]1>C(O)(=O)C>[CH3:53][O:52][C:45]1[CH:46]=[C:47]([O:50][CH3:51])[CH:48]=[CH:49][C:44]=1[CH2:43][NH:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@H:25]3[C@H:26]4[C@H:30]([O:29][C:28]([CH3:32])([CH3:31])[O:27]4)[C@@H:23]([CH2:22][N:20]([CH3:21])[CH:18]4[CH2:17][CH:16]([CH2:15][CH2:14][C:13]5[NH:12][C:3]6[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=6[N:1]=5)[CH2:19]4)[CH2:24]3)[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reaction time: 1 h

Procedure:
N-(2-amino-4-(trifluoromethyl)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.38 g, 0.50 mmol) and Acetic acid (5 ml) were stirred overnight at 65° C. The volatiles were removed in vacuo and remaining water was removed by azeotropic distillation with ethanol followed by 1 hour on high vacuum. The resulting residue was partitioned between NaHCO3 (saturated) and DCM. The aqueous layer was extracted (3×) and combined organics were dried with MgSO4, filtered, concentrated and then purified by flash chromatography (DCM/7N NH3 in MeOH 93:7) to yield an off white foam.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([OH:59])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.COC(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([O:59][CH3:60])[CH2:40]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Solvent: CO
Solvent: COC(OC)OC
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(OC)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 65 °C
Yield: 104.3 %

Procedure:
To a solution of 41 (85 mg, 105 μmol) in anhydrous MeOH (1 mL) and trimethylorthoformate (0.5 mL) was added 4-toluenesulfonic acid (15 mg). The mixture was heated in a closed vial at 65° C. for 2 h, cooled to rt, evaporated, loaded onto a preparatory TLC plate, and developed using 15% EtOAc in petroleum ether to yield 42 (75 mg, 91% yield) as two diastereomers. LCMS m/z 847 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:30](O)=[O:31])=[N:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:23]3[C:22]([Cl:21])=[CH:27][C:26]([C:28]#[N:29])=[CH:25][N:24]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I yielded the 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as a white solid. MS (ISP): m/z=452.1 [M+H]+.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13]([CH3:14])=[O:26])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:2][CH:3]([CH2:4]1)[CH2:5]2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(NC23CC(C2)C3)ncc1C(N)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(NC23CC(C2)C3)ncc1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a stirring solution of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carboxamide (410 mg, 1.638 mmol) in chloroform (39.0 mL) was added portionwise, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (514 mg, 1.965 mmol). The resulting pale yellow solution was stirred at ambient temperature for two nights under nitrogen. The reaction mixture was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (15 mL) was added to these solids and the slurry was stirred at room temp for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (397 mg, 1.491 mmol, 91% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-9.14 (m, 2H), 7.93-8.11 (m, 1H), 7.41-7.54 (m, 1H), 2.68-2.79 (m, 3H), 2.43-2.48 (m, 1H), 2.02-2.21 (m, 6H). MS (ESI) m/z 267.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[NH2:16][C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1ccccc1C=O
Reactant: COc1ccc(N)cc1OC
Product: COc1cc(N)c(C(=O)c2ccccc2OC)cc1OC

Procedure:
(2-amino-4,5-dimethoxyphenyl)-(2-methoxyphenyl)-methanone (Xaa) was prepared by reacting 2-methoxybenzaldehyde with 0.0196 moles of 3,4-dimethoxy aniline in a manner analogous to Example 1. MH+/Z=288.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[C:17]([F:24])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]=1[F:24])(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Yield: 88.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 500 mg, 2.8216 mmol) was reacted with 1-(4-bromo-2-fluoro-phenyl)-ethanone (679.9 mg, 3.1038 mmol), 1,4-dioxane (50 mL), copper iodide (53.6 mg, 0.28216 mmol), trans-1,2-diamino cyclohexane (97.09 mg, 0.84650 mmol) and potassium phosphate (1.49 g, 7.0541 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 780 mg of 1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (88.2% yield).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH3:9].Cl>CN(C)C=O.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>[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([C:11]2[O:10][C:7]3[CH:6]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=2)=[CH:14][CH:13]=1)[CH3:9]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The compound prepared in Reference Example 1 (2.64 g), dichlorobis(triphenylphosphine)palladium (II) [PdCl2(PPh3)2] (0.635 g) and triethylamine (10 ml) were added to a solution of 4-iodobenzoic acid ethyl ester (5 g) in dimethylformamide (10 ml). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The precipitated crystals was washed with hexane/diethyl ether and dried to give the title compound (3.6 g) having the following physical data.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8](#[N:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[OH-].[Na+]>[Cl-].[Cl-].[Zn+2].CC(=O)CC>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:4]2[CH2:3][CH2:2][S:1][CH2:6][C:5]=12
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCSCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: Nc1c2c(nc3ccccc13)CCSC2

Procedure:
Tetrahydrothiopyran-4-one (10.0 g) was mixed with anthranilonitrile (5.08 g) and the mixture warmed at 60° until a homogeneous solution was obtained. Freshly fused ZnCl2 (8.2 g) was then added portionwise and the temperature of the reaction mixture raised to 120°. After 2 hours it was cooled and distributed between 10% NaOH and 2-butanone. The organic phase was separated, dried, and concentrated and the crude product triturated with Et2O and then passed over a silica gel column (5% Et3N-ethyl acetate). The product-containing fractions were concentrated and the product recrystallized from toluene to give 3.66 g, mp 214°-216°.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[CH2:20]([C:14]([CH3:24])([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:26][CH:25]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [Pd]
Product: CCCCC(C)(Cc1ccc(O)cc1)C(=O)OCC
Yield: 100.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 2-(4-benzyloxybenzyl)-2-methylcaproate (3.95 g), which is the product of Reference example 10(a), and palladium on carbon (5%, 0.40 g) and the reaction mixture was treated to afford the desired compound (2.95 g) as a syrup.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.P([O-])(O)(O)=[O:25].[Na+]>ClCCl>[CH2:1]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[O:25][CH2:22]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: C=CCCCCCCCCCOCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C(=COCc1ccc2c(c1)OCO2)CCCCCCCC1CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 11.0 g. (0.036 mole) of 10-undecenyl piperonyl ether and 5.0 g. (0.036 mole) of sodium dihydrogen phosphate monohydrate in 100 ml. of dichloromethane, was added 7.6 g. (0.036 mole) of m-chloroperbenzoic and dissolved in 200 ml. of dichloromethane. After stirring at ambient temperature for 24 hours, the mixture was filtered and washed with an aqueous sodium bicarbonate solution. After drying the dichloromethane solvent was removed by evaporation. The crude product obtained in this way was purified by passing through a silica gel chromatographic column using first a 5% ether in hexane eluent and then a 50% ether in hexane eluent to recover the 10,11-epoxyundecenyl piperonyl ether which weighed 5 g. An infrared spectra had strong adsorption peaks at 3.4, 3.5, 6.7, 6.95, 7.9-8.0, 9.1, 9.6, 10.8 and 12.4 microns.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:22]1[CH:30]=[C:29]([O:31][CH3:32])[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])(=[O:13])=[O:12].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:14]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]([OH:3])[C:22]1[CH:30]=[C:29]([O:31][CH3:32])[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)(=[O:12])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COc1cc(C(O)c2ccccc2S(=O)(=O)Nc2ccccc2C)cc2c1OCO2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(O)c1cc(OC)c2c(c1)OCO2
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
Sixty percent sodium hydride suspension in oil (0.422 g, 10.55 mmol) was washed with tetrahydrofuran and was added to tetrahydrofuran (175 mL). To this was added 2-[hydroxy-(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]-N-o-tolyl-benzenesulfonamide (4.1 g, 9.59 mmol). After stirring for 30 minutes, methyl bromoacetate (1.09 mL, 11.5 mmol) was added followed by stirring at reflux for 18 hours. The mixture was evaporated to an oil in vacuo, and the residue was resuspended in ethyl ether, washed with 1N citric and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid. The material was chromatographed on 300 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo from ethyl ether giving a solid, 4.29 g, 89.5% yield. NMR spectra and elemental analysis were consistent with the structure.