Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)=[O:23])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Nc1nccs1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC2=NCCS2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Aminothiazole (38 mg, 0.37 mmole) was dissolved in dry tetrahydrofuran (6.5 ml) followed by addition of triethylamine (77 mg, 0.76 mmole) and 4-t-butylbenzoyl chloride (151 mg, 0.76 mmole). The reaction was stirred overnight at room temperature, and then the solvent removed under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile gradient), giving [4-(tert-butyl)phenyl]-N-(1,3-thiazolin-2-yl)carboxamide. The product was characterized by HPLC-MS.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[N+:21]([C:24]1[CH:25]=[C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)([O-:23])=[O:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:36]2[CH2:37][CH2:38][N:33]([C:26]3[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[CH2:34][CH2:35]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc([N+](=O)[O-])c1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Yield: 64.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dinitrophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.[N:15]([O-:17])=[O:16].[Na+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cc(C)nc(N2CCOCC2)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCOCC2)nc(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To 4-(4,6-dimethyl-pyridin-2-yl)-morpholine (9.4 g) dissolved in trifluoroacetic acid (250 mL) cooled to 0° C. was added sodium nitrite (3.54 g) over 15 minutes and the reaction mixture was then stirred 15 minutes at 0° C. The reaction mixture was concentrated in vacuo to app. 100 mL and the pH adjusted to 11 with concentrated aqueous sodium hydroxide (150 mL). Brine (200 mL) was added and the mixture was extracted with diethyl ether (4×150 mL), the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 4:1) to furnish 2.01 g (17% yield) of the title compound as a yellow solid. GC-MS (m/z) 237 (M+); tR=7.69. 1H NMR (500 MHz, DMSO-d6): 2.28 (s, 3H), 2.39 (s, 3H), 3.60 (m, 4H), 3.67 (m, 4H), 6.72 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Yield: 94.7 %

Procedure:
A dry reaction flask was charged with 4-nitrophenol (3.858 g, 27.75 mmol), anhydrous K2CO3 (8.29 g, 60 mmol) and acetone (250 mL). To this heterogeneous mixture was added 2-pyridylmethylbromide hydrobromide (7.0 g, 27.75 mmol) and refluxed for 24 h. From the resulting reaction mixture, 200 mL of acetone was removed under reduced pressure. The resulting residue was then diluted with ice-water (1 liter), the solid crushed out was filtered, washed with water and dried well to give 2-[(4-nitrophenoxy)methyl]pyridine (6.05 g, 95% yield). 1H NMR (CDCl3): δ 8.61 (d, 1H, J=4.8 Hz), 8.19 (d, 2H, J=9.0 Hz), 7.72 (m, 2H), 7.46 (d, 1H, J=7.8 Hz), 7.25 (m, 1H), 7.05 (d, 2H, J=9.3 Hz), 5.28 (s, 2H); LCMS (m/z): 231 (MH+).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)cc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-5-methoxy-1-benzofuran (360 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (305 mg) synthesized in Example 1(2), sodium iodide (291 mg) and N,N-dimethylacetamide (10 mL) was added sodium carbonate (206 mg), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=11:9, volume ratio) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (2.5 and ethanol (2.5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (5 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (96.0 mg, 17%) as a yellow solid.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@@H:12]([CH2:13][OH:14])[O:11][CH2:10][CH2:9][C@@:6]21[O:8][CH2:7]2)[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:15]([Si:3]([CH2:1][CH3:2])([CH2:17][CH3:18])[O:4][C@@H:5]1[C@@H:12]([CH:13]=[O:14])[O:11][CH2:10][CH2:9][C@@:6]21[O:8][CH2:7]2)[CH3:16]
Reactant: CC[Si](CC)(CC)O[C@@H]1[C@@H](CO)OCC[C@@]12CO2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H]1[C@@H](C=O)OCC[C@@]12CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
A stirred suspension of alcohol 34 (15 mg, 0.05 mmol) and 4A° MS (15 mg) in CH2Cl2 (1 mL) at 0° C. was treated sequentially with N-methylmorpholine-N-oxide (9.6 mg, 0.08 mmol) and tetrapropylammonium perruthenate (1.9 mg, 5.47 μmol). After 10 min at 0° C., the resulting suspension was allowed to warm to room temperature and stirred for 30 min by which time TLC showed that all of starting material has been consumed. The suspension was directly loaded onto silica column and eluted with 40% ethyl acetate in hexane to give 7 mg (47%) of 35 as liquid. 1H NMR (400 MHz, CDCl3) δ 9.76 (d, J=0.9 Hz, 1H), 4.16 (ddd, J=11.5, 5.0, 2.7 Hz, 1H), 3.95-3.76 (m, 2H), 3.65 (td, J=11.5, 2.6 Hz, 1H), 3.05 (dd, J=5.3, 1.4 Hz, 1H), 2.59 (d, J=5.4 Hz, 1H), 2.21-2.07 (m, 1H), 1.59 (t, J=2.6 Hz, 1H), 0.98-0.89 (m, 10H), 0.66-0.55 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
(S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol, Example 29, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.129 mL, 2.47 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.356 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to provide 0.53 g (78%) of the pure titled compound as a white foam: mp 65-78° C. APCI-MS m/z 528.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:4](C(OCC2C=CC=CC=2)=O)[C:3]1=[O:27]>Br.C(O)(=O)C>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:27]
Reactant: CN1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1=O
Agent: Br
Solvent: CC(=O)O
Product: CN1C[C@@H](C(=O)OCc2ccccc2)NC1=O
Yield: 83.3 %

Procedure:
10 g of benzyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate and 40 ml of a hydrogen bromide-acetic acid solution are treated in the same manner as described in Preparation 4-(3), whereby 5.3 g of benzyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 83.3%
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[Cl:10]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl>[Cl:10][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(CCl)c1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of 121.18 g (1 mole) of 2,4,6-collidine in 400 ml of chloroform was heated at reflux while adding in portions 140 g (0.6 mole) of trichloroisocyanuric acid (min. 90% available chlorine) over 4 hours and stirring was continued for another 30 minutes and then cooled and filtered. The filtrate was admixed with 150 ml of 10% HCl to transform the product into the aqueous phase. The decanted acid aqueous phase was mixed with 150 ml of ethyl acetate and was made alkaline with sodium hydroxide. The decanted aqueous phase was extracted with 100 ml of ethyl acetate. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 45 g (28.9%) of 2-chloromethyl-4,6-dimethyl pyridine with a Cl content of 22.78% (theoretical 22.78%) and a boiling point of 64° to 70° C. at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH3:28][CH:29]=[CH:30][CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:32][CH2:31][CH2:30][CH:29]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 32, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylmethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: OCc1ccc(O)cc1
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Temperature: 38 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol), 2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38° C. Potassium L-butoxide (45.29 g, 403.6 mmol) was added, and the mixture was heated to reflux at 132° C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 h. When water collection slowed (around 2.5 h) then portions of solvent (30-40 mL each) were removed every thirty minutes. During the water collection and solvent removal the temperature rose from 132° C. to 149° C. After 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100° C. water (200 mL) was added, and the solution was allowed to cool to room temperature. Solvent was removed on a rotary evaporator under vacuum until 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) were added and the layers were separated (layer separation was poor, but addition of 20% aqueous NaCl was ineffectual). The aqueous layer was extracted with EtOAc (200 mL), and the combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which EtOAc was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, and the product crystallized to yield a beige solid (112.36 g, 71% yield, >98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating more fully to a solution and adding heptane to crystallize. NMR. E.A.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[NH:28][C:29]4[CH:30]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=4)=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-amino benzamide as the aniline component. (9%, MS=513.2 (M+H))
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:30]([CH:31]2[CH2:33][CH2:32]2)=[N:29][N:28]=[C:27]1[SH:34].[I-].[K+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>CN(C)C=O.C(OCC)(=O)C.O>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:34][C:27]3[N:26]([CH3:25])[C:30]([CH:31]4[CH2:33][CH2:32]4)=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(S)nnc1C1CC1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Agent: O=C(O)/C=C/C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)nnc1C1CC1

Procedure:
0.4 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (1.14 mmol), 0.2 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (1.29 mmol), 0.07 g lithium-hydroxide (2.92 mmol) and a spatula tip of potassium iodide were stirred in 20 ml of dimethylformamide overnight at room temperature and for an additional 3 h at 40° C. After addition of water and ethyl acetate, the organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel using dichloromethane-methanol (0-2%). Fractions containing the product were combined and the solvents were evaporated. The residue was dissolved in isopropanol and 1 equivalent of fumaric acid was added. The solvent was evaporated and the residue was dissolved in diisopropylether to which some drops of isopropanol were added upon warming, thereby forming a precipitate. After cooling the precipitate was collected by filtration and dried. Yield: 0.04 g (6%)
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])=O.O1CCCC1.O1CCCC1.B.CO>O1CCCC1>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][CH2:4][CH2:3][CH:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:1])([O-:16])=[O:15]
Reactant: O=C(CC(O)c1ccccc1)NCc1ccccc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccccc1CNCCC(O)c1ccccc1
Reaction time: 1 h

Procedure:
3-Hydroxy-N-(2-nitrobenzyl)-3-phenyl propionic acid amide (3.19 g, 10.6 mmol) was dissolved in tetrahydrofuran (50 ml) and under ice cooled condition, 1 M tetrahydrofuran-borane tetrahydrofuran solution (27.0 ml, 27.0 mmol) was added dropwise thereto. After the dropwise addition was finished, the reaction mixture was returned to room temperature and stirred for one hour, then heated to reflux for six hours and allowed to cool. Methanol (30 ml) was added thereto under ice cooled condition and heated to reflux for 30 minutes. After allowed to cool, the solvent was evaporated and 0.5 N hydrochloric acid water (30 ml) was added. After extracted with diethyl ether, the aqueous layer was adjusted to pH 8 with a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 3-(2-nitrobenzylamino)-1-phenylpropanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:24]1([S:30]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), benzenesulfonyl chloride (0.30 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH:24]4[CH2:25][CH:21]([CH:22]=[CH:23]4)[CH:20]2[CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=1>C(OCC)(=O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:13]1([C:16]23[CH:24]4[CH2:25][CH:21]([CH2:22][CH2:23]4)[CH:20]2[CH2:19][NH:18][CH2:17]3)[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=1
Reactant: Clc1ccc(C23CNCC2C2C=CC3C2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Product: c1ccc(C23CNCC2C2CCC3C2)cc1
Reaction time: 17 h

Procedure:
A 0.49 g portion of 3a-(4-chlorophenyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindole fumarate was suspended in 30 ml of ethyl acetate, washed twice with 10% sodium bicarbonate solution, dried with brine and 47 mg of 5% palladium on calcium added. The mixture was stirred under one atmosphere of hydrogen for 17 hours, then filtered, washed with 10% sodium bicarbonate, dried and evaporated, giving 0.25 g of the free base of the desired compound as a brown oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(C)(C)C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C(C)(C)C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.45 g of 4,5-bis(4-methoxyphenyl)-2-(4-tert-butylphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 4.17 g of 4,5-bis(4-methoxyphenyl)-2-(4-tert-butylphenylsulfinyl)imidazole as an amorphous foam.