Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:31][CH2:30][C:23]3([NH:27]C(=O)N[C:24]3=[O:29])[CH2:22][CH2:21]2)=[O:19])=[C:12]([Cl:32])[C:11]=1[Cl:33].[O:34](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C(N(CC)CC)C.[OH-].[Na+]>COCCOC.CN(C1C=CN=CC=1)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:31][CH2:30][C:23]([NH2:27])([C:24]([OH:34])=[O:29])[CH2:22][CH2:21]2)=[O:19])=[C:12]([Cl:32])[C:11]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccccc1Sc1ccc(/C=C/C(=O)N2CCC3(CC2)NC(=O)NC3=O)c(Cl)c1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COc1ccccc1Sc1ccc(/C=C/C(=O)N2CCC(N)(C(=O)O)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a suspension of Example 355 (700 mg, 1.4 mmol) in DME (10 mL) was added a solution of (BOC)2O (1.51 g, 6.9 mmol) in DME (5 mL), triethylamine (0.23 mL, 1.7 mmol) and DMAP (9 mg, 0.07 mmol). The reaction mixture was stirred at room temperature overnight. Additional triethylamine (0.23 mL) and DMAP (30 mg) were added, and the mixture was heated at 60° C. for 6 hours. After aqueous work up, the crude product was suspended in DME (5 mL) and water (5 mL) containing 200 mg of NaOH. The suspension was stirred for 5 hours at room temperature, and separated by HPLC to give the title compound (300 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 1.78 (m, 2H), 2.10 (m, 2H), 3.60 (m, 2H), 3.80 (s, 3H), 3.86 (m, 2H), 6.58 (d, 1H), 7.10 (d, 1H), 7.25 (d, 1H), 7.28 (d, 1H), 7.50 (d, 1H), 7.58 (t, 1H), 7.77 (d, 1H), 7.80 (d, 1H), 8.50 (br s, 2H). MS (ESI+) m/z 481 (M+H)+. Anal calcd for C22H22N2Cl2SO4.0.75H2O: C, 47.34; H, 4.06; N, 4.60. Found: C, 47.31; H, 4.05; N, 4.43.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
21-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (412 mg) in acetone (20 ml) was stirred during dropwise addition of Jones reagent (0.4 ml) at room temperature. After 10 minutes, the reaction mixture was poured onto water extracted with chloroform and the combined chloroform extract was washed with water dried (MgSO4) and evaporated. The residue was crystallised from ether/petrol to give title compound (350 mg) as white microcrystals mp 170° [αD ] + 132° (ε 1.1).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-fluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.69 (d, J=5.9 Hz, 2H), 5.98 (bs, 1H), 6.32 (s, 1H), 6.94 (t, J=8.3 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.36-7.42 (m, 2H), 7.61 (t, J=7.5 Hz, 1H), 8.58 (d, J=5.4 Hz, 1H); MS (ESI) m/z 324.0 (M+1)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(COC)OC>[C:3]1([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(Cc1ccccc1)c1ccccc1

Procedure:
Sodium hydride (8.4 g., 0.2 mole, oil dispersion) is suspended in glyme (400 ml.) and phenyl acetone (26.8 g., 0.2 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for one hour then cooled in a cold water bath. A solution of benzyl chloride (25.3 g., 0.2 mole) in glyme (50 ml.) is added then the mixture is refluxed for 12 hours. Removal of the inorganic salts by filtration followed by vacuum distillation of the residue gives 31.06 g., b.p 104°-107°/0.1 mm
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].CS(O)(=O)=O.[OH:10][C@@H:11]1[CH2:16][O:15][C:13](=[O:14])[CH2:12]1>O>[OH:10][C@H:11]([CH2:12][C:13](=[O:14])[O-:15])[CH2:16][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C
Reactant: O=C1C[C@H](O)CO1
Agent: CS(=O)(=O)O
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an aqueous solution of trimethylamine (250 mL), 25% by weight solution of trimethylamine in water, is added (S)-3-hydroxybutyrolactone methane sulfonate (98 g, 0.5 mol) prepared as described above. The resulting solution is stirred at room temperature 1 hr, and then heated at 100° C. in a sealed vessel for 16 hrs. Upon cooling the solution to room temperature, the reaction mixture is evaporated to dryness in vacuo using ethanol and toluene (5:1) to remove residual water by azeotropic distillation. The crude L-carnitine is triturated with anhydrous acetone (100 ml) and the purified L-carnitine thus produced is collected by filtration. [α]D22 -31° (c 10.0, H2O).
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1(=[O:18])[CH2:17][CH2:16][CH2:15]C1.N>CCOCC.[Zn]>[OH:18][C:13]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)CC1(O)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
Trimethylchlorosilane (1.14 mL, 8.92 mmol) was added by syringe to a suspension of zinc powder (7.97 g, 0.122 mol) in absolute Et2O (200 mL). The mixture was stirred for 15 minutes at room temperature. The mixture was then heated to reflux, the heat source was removed, and ethyl bromoacetate (10.3 mL, 92.9 mmol) was added at such a rate that the ether solution gently boiled. The mixture was refluxed one hour then stirred for an additional hour at room temperature. A solution of cyclopentanone (6.00 g, 75.9 mmol) in ether (30 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. After being one hour of stirring at room temperature, the mixture was poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether and the combined phases were dried over K2CO3. Filtration and evaporation of the solvent yielded the title compound as a colorless oil (6.50 g, 54%). 1H-NMR (400 MHz, CDCl3) δ 1.29 (3H, t, J=7.3 Hz), 1.47-1.64 (1H, m), 1.76-1.87 (1H, m), 1.93-2.06 (2H, m), 2.12-2.22 (2H, m), 2.67 (2H, s), 3.70 (1H, s), 4.19 (2H, q, J=7.3 Hz).
Reaction SMILES: [CH:1]1([CH:7]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[CH3:16][O:15][C:13](=[O:14])[NH:12][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][C:31]([C:29]3[CH:30]=[C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)[N:26]=[C:27]([NH2:41])[N:28]=3)=[CH:32][CH:33]=2)[CH2:38]1)=[O:11]
Reactant: COC(=O)NC(CC(=O)O)C1CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: COC(=O)NC(CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)C1CCCCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-cyclohexyl-3-[(methoxycarbonyl)amino]propanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=536.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]=1.O(Cl)Cl.[C:12]([Cl:16])(Cl)([Cl:14])[Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([Cl:16])([Cl:14])[Cl:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClOCl
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reaction time: 120 h
Yield: 83.9 %

Procedure:
p-Chlorotoluene (1.17 g, 0.0092 mole) and dichlorine monoxide (2.40 g, 0.028 mole) in carbon tetrachloride (35 ml) were mixed and stored in a stoppered bottle at room temperature for 5 days. The initial reaction ws exothermic. The product was dried (MgSO4) and the solvent removed on a rotary evaporator to give 4-chlorotrichloromethylbenzene as a pale yellow oil (2.00 g, purity by HPLC 88.78%; yield 83.9%), containing a small amount of dichlorotrichloromethylbenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1CCc2cc(C(=O)C(C)(C)C)sc2CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
A solution of the product from Example 1, step (d) (160 mg, 0.71 mmol) in dichloroethane (5 ml) at 0° C. was treated with trimethyl acetyl chloride (0.17 ml, 1.42 mmol) and AlCl3 (190 mg, 1.42 mmol). The reaction mixture was allowed to stir at 0° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture was quenched by the addition of saturated solution of NaHCO3 (30 ml) and extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and solvent evaporated in vacuo to give a tan oil. The crude oil was purified by silica gel chromatography (0% to 50% EtOAc in Hex) to give the subtitle compound as a clear oil (60 mg, 27%). MS: ESI (positive): 310 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.C=O.O.[C:42]([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:42])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
Benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (3.2 g, 6.12 mmol) was dissolved in methanol (32 ml). Formaldehyde in water (37%) (0.92 ml, 12.3 mmol) was added and stirred for 45 min before adding sodium cyanoborohydride (0.54 g, 8.57 mmol) portionwise. The reaction was stirred for 2 h at r.t. before adding water (1 ml) and evaporating off the solvent at r.t. The residue was purified by chromatography with 7M ammonia in methanol/DCM to give the desired compound as a yellow oil (mix of diastereomers) (2.05 g, 62%, 82% pure): MS (ESI+) for C28H36N6O5 m/z 537.6 [M+H]+; LC purity 82% (ret. time, 1.60 min); 1H NMR (500 MHz, CDCl3) δH 8.32-8.38 (m, 1H), 7.91-7.97 (m, 1H), 7.32-7.39 (m, 5H), 6.05-6.10 (m, 1H), 5.61 (br. s., 2H), 5.53 (ddd, J=16.5, 6.4, 1.8 Hz, 1H), 5.11 (m, 2H), 4.93-5.00 (m, 1H), 4.32-4.40 (m, 1H), 2.50-2.88 (m, 1H), 2.37-2.49 (m, 2H), 2.21-2.30 (m, 2H), 2.10 (m, 3H), 1.91-2.04 (m, 1H), 1.73-1.79 (m, 2H), 1.64-1.72 (m, 2H), 1.56-1.63 (m, 4H), 1.41 (s, 3H), 1.15 (q, J=9.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:5]([CH3:9])[C:6]([OH:8])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[C:6]([OH:8])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=1)=[O:18]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (1 g, 4 mmol) in anhydrous tetrahydrofuran (10 mL), trifluoroacetic anhydride (3.3 g, 15.7 mmol) was added in one portion followed by the addition of triethylamine (3.3 mL, 24 mmol) dropwise. After being stirred at room temperature for 4 hours, the mixture was acidified to pH 3 with 5% aqueous hydrochloric acid and extracted with ethyl acetate (30 mL). The organic layer was concentrated in vacuo. The residue was dissolved in methanol (15 mL). The resulting solution was cooled to 0° C., then treated with sodium borohydride (380 mg, 10 mmol), and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and 5% aqueous hydrochloric acid (20 mL). The aqueous phase was separated and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 10% ethyl acetate in hexanes) to afford 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (740 mg, 80%) as a pale solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=2)[CH:13]=1
Reactant: Nc1ccccc1
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)c1

Procedure:
To a solution of 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg) and triethylamine (0.135 ml) in tetrahydrofuran (2 ml) was added aniline (2 ml). The mixture was stirred under reflux for 6 hours and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The precipitate was triturated with diisopropyl ether, collected by filtration and dried to give 4-(4-methoxypyridin-2-yl)-2-nitro-N-phenylaniline (235 mg).
Reaction SMILES: C([Li])CCC.CN(C)N=C(C)C.I[CH2:14][CH2:15][CH2:16][C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20].I[CH2:24][C:25]1([CH2:33][CH2:34][CH3:35])[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27][CH2:26]1.CC1(C)OCC(CCC(=O)CCCCC#C[Si](C)(C)C)(CCC)CO1.O=C(C)CCCCC#C[Si](C)(C)C.Cl>O1CCCC1>[CH2:33]([C:25]12[CH2:24][CH2:31][C:28]([CH2:32][CH2:14][CH2:15][CH2:16][C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])([O:29][CH2:30]1)[O:27][CH2:26]2)[CH2:34][CH3:35]
Reactant: CCCC1(CI)COC(C)(C)OC1
Reactant: C[Si](C)(C)C#CCCCI
Agent: CC(=O)CCCCC#C[Si](C)(C)C
Agent: CC(C)=NN(C)C
Agent: CCCC1(CCC(=O)CCCCC#C[Si](C)(C)C)COC(C)(C)OC1
Solvent: C1CCOC1
Product: CCCC12CCC(CCCCC#C[Si](C)(C)C)(OC1)OC2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (19.0 ml., 1.6M solution in hexane) was added dropwise to a stirred solution of acetone N,N-dimethylhydrazone (2.6 g.) (ref. R. H. Wiley at al J. Org. Chem. 1957, 22, 204) in dry tetrahydrofuran (40 ml.) at -70°, under a current of nitrogen. The resulting solution was stirred for 30 minutes and a solution of 5-iodo-1-trimethylsilylpent-1-yne (8.1 g.) in dry tetrahydrofuran (30 ml.) was added dropwise and the reaction mixture was stirred at -70° for 1 hour, allowed to warm to 0° and stirred for 2 hours. The reaction mixture was cooled to -70° and a second portion of n-butyllithium (19 ml. 1.6M solution in hexane) was added dropwise. The mixture was stirred at -70° for 15 minutes, allowed to warm to 0° and stirred for 30 minutes. A solution of 5-iodomethyl-2,2-dimethyl-5-n-propyl-1,3-dioxane (9.0 g. European Patent 216625) in dry tetrahydrofuran (30 ml.) was added. The mixture was stirred at 0° for 30 minutes and 48 hours at 20°. The solvent was removed in vacuo and the residue was poured into water. The aqueous mixture was extracted with diethyl ether and the ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Chromatography of the residue on silica, eluting with diethyl ether:hexane 1:9 gave a yellow oil which consisted of 2,2-dimethyl-5-(3-oxo-9-trimethylsilylnon-8-ynyl)-5-n-propyl-1,3-dioxane and 7-oxo-1-trimethylsilyloct-1-yne in the ratio of 3:1 (1.4 g.). The above mixture in tetrahydrofuran (25 ml.) and hydrochloric acid (50 ml., 1N solution) was stirred vigorously at 20° for 1 hour. The tetrahydrofuran was removed in vacuo and the residue was extracted into diethyl ether. The ethereal extracts were dried over magnesium sulphate and the solvent was removed in vacuo. 4-n-Propyl-1-(6-trimethylsilylhex-5-ynyl) 2,6-dioxabicyclo[2.2.2]octane was obtained as a colourless oil (1.06 g.) and was used without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.N([O-])=O.[Na+].NC(N)=O.[BrH:21]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].[Cu]>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CCc1cc(N)ccc1[N+](=O)[O-]
Reactant: Br
Agent: [Cu+2]
Agent: [Cu]
Agent: NC(N)=O
Solvent: O
Product: CCc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
1.66 g (10 mmol) of 5-amino-1-ethyl-2-nitrobenzene (2) are added to a mixture of 12.5 ml of 48% hydrobromic acid and 7.5 ml of H2O heated to 60° C. and cooled rapidly in an ice bath. At a temperature below 5° C., the mixture is subjected to diazotisation with 760 mg (11 mmol) of sodium nitrite in 10 ml of H2O. After 10 minutes, a pinch of urea from a spatula is added and the mixture stirred for another 5 minutes in the ice bath. This reaction mixture is fed into a suspension of 1.5 g (6 mmol) of copper sulfate pentahydrate and 600 mg (9.4 mmol) of copper powder in 12.5 ml of 48% hydrobromic acid and 7.5 ml of H2O and heated to 80° C. for 30 min. After cooling, the reaction solution is extracted 3 times with 50 ml each of EE and the combined organic phases washed once with 50 ml each of 1 n NaOH and H2O. After drying over Na2SO4, concentration by means of a rotary evaporator is carried out. The crude product is placed on silica gel and purified by flash chromatography (40 g of silica gel, 3.5×13 cm, LM: PE/EE, cond. PE, gradient: 150 ml PE, 600 ml 150: 1, 150 ml 150:2). 1.55 g (6.7 mmol, 67%) of (7) are obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:12][CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:1][C:2]1[C:9]([O:10][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)CBr
Reactant: N#Cc1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)COc1cccc(C#N)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A 100 mL round bottom flask was charged with a magnetic stir bar, 2-fluoro-3-hydroxybenzonitrile (0.500 g, 3.65 mmol), MeCN (13.89 ml), 1-bromo-2-methylpropane (0.699 ml, 7.29 mmol), and K2CO3 (1.008 g, 7.29 mmol). The mixture was then placed in an oil bath and heated to 60° C. with stirring overnight. This mixture was then cooled to rt, filtered through a bed of Celite, and conc. In vacuo. The crude material was purified via silica gel chromatography (40 g) using ethyl acetate/hexanes (1:4) as eluent to afford pure 2-fluoro-3-isobutoxybenzonitrile (0.610 g, 87%) as a colorless oil. M/z 194.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4C=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[NH2:39]C1C=C(C(F)(F)F)C=CN=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:28]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:31][N:39]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1NC(=O)c1cccc2c(N)nccc12
Yield: 7 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 2-amino-4-(trifluoromethyl)pyridine instead of aniline in Step (1) of Example 2 to obtain the title compound (3.5 mg, 7%).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:15][NH:16][C:17]([NH:19][CH3:20])=[O:18].C(=O)(O)[O-].[Na+]>Cl.C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[N:19]([CH3:20])[C:17](=[O:18])[N:16]([CH3:15])[C:10](=[O:12])[CH:9]=2)[CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: CNC(=O)NC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1c(-c2cccnc2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.2 %

Procedure:
To a mixture of ethyl nicotinoylacetate (2.30 g) and N,N'-dimethylurea (1.05 g) were added conc. hydrochloric acid (a few drops) and ethanol (1 ml) and the mixture was stirred at 110°-115° C. for 4 hours under reduced pressure (30 mmHg). After being cooled to ambient temperature, the solution was adjusted to pH 7.0 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to give 6-(3-pyridyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (0.91 g).