Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([N:6]([C:10](=[O:22])[C@H:11]([OH:21])[C@@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]Cl)=[CH:4][CH:3]=1.CN(C=O)C>CC(O)(C)C.CS(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([N:6]2[CH2:7][CH2:8][O:21][C@H:11]([C@@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]2=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)N(CCCl)c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(Cl)cc2)C1=O
Yield: 24.9 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 60-4 (1.78 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 60-5 (400 mg) as a pale yellow amorphous solid.
Reaction SMILES: P(Cl)(Cl)(OC)=O.[CH3:7][O:8][C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([NH2:19])=O)[CH:12]=[CH:11][C:10]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1.C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:7][O:8][C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]#[N:19])[CH:12]=[CH:11][C:10]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Agent: COP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(/C=C/C#N)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 85.8 %

Procedure:
Methyl dichlorophosphate (33 ml) was added dropwise to a suspension of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (42.96 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (112 ml) in methylene chloride (400 ml) under ice-cooling over 20 minutes. The reaction solution was stirred at the same temperature for 10 minutes and at room temperature for further 35 minutes. Then, a saturated sodium bicarbonate solution (200 ml) was added to the reaction solution, and the reaction solution was stirred at room temperature for 10 minutes. Water was added to the reaction solution. Then, the reaction solution was filtered and the organic layer in the filtrate was separated. The aqueous layer was reextracted with methylene chloride (twice). The combined organic layers were dried over anhydrous magnesium sulfate and purified by short silica gel column chromatography (carrier: Chromatorex NH; elution solvent: methylene chloride). The eluted fraction was concentrated. The resulting residue was triturated with ethyl acetate and tert-butyl methyl ether and dried under reduced pressure overnight to obtain 34.28 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[NH:12][C:11](=[S:15])[O:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]=[O:17].O>CO.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:16][OH:17])[C:11](=[S:15])[O:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-n2oc(=S)[nH]c2=S)cc1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-n2oc(=S)n(CO)c2=S)cc1
Reaction time: 2 h

Procedure:
2-(4-Cyanophenyl)-1,2,4-oxadiazolidin-3,5-dithione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-cyanophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dithione.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10](S)[CH3:11].[F:13][C:14]1[C:27]([NH:28][C:29]([CH:31]2[CH2:35][CH2:34]C[N:32]2C(OCC2C=CC=CC=2)=O)=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1.[OH-].[Na+].O>C(Cl)Cl.O>[F:13][C:14]1[C:27]([NH:28][C:29]([CH:31]2[NH:32][CH2:10][CH:11]3[CH:35]2[CH2:34]3)=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3CCCN3C(=O)OCc3ccccc3)cc21
Reactant: CCS
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3NCC4CC43)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
To a solution of boron trifluoride etherate (1.57 gm, 10.8 mmol) and ethanethiol (2.31 mL, 1.94 gm, 32.32 mmol) under N2, at room temperature was added dropwise a solution of the compound of Step F, Example 3, (500.0 mg) in CH2Cl2 (1 mL). The resultant clear solution was stirred at room temperature for 48 hours and the reaction was scrubbed with a bleach/50% NaOH/H2O-20%. 30 mL of water was added dropwise at room temperature followed by CH2Cl2 (30 mL). The aqueous layer was separated and basified to pH 10 using 50% NaOH. Additional 30 mL of CH2Cl2 was added and the organic layer was separated, dried (MgSO4) and evaporated to dryness to give the title compound of Step G as a white solid (200 mg), 57%; m.p. 196°-198° C.; IR (nujol, cm-1): 1676.0 (C=O), 3357.7 and 3301.7 (NH); 1H NMR δ: 0.08-0.09 (m,1H), 0.71-0.77 (m,1H), 1.41-1.43 (m,1H), 2.01-2.08 (m,1H), 2.11-2.17 (broad s, 1H), 2.31-2.32 (m,1H), 3.02 (s,2H), 3.72 (s,1H), 4.61 (s,2H), 4.75-4.81 (dd,2H), 6.79-6.81 (d,1H), 8.44-8.46 (d,1H), 9.85 (broad s,1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[O:21]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1>C(#N)C>[O:21]1[C:25]2([CH2:30][CH2:29][N:28]([C:7]3[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=3[F:1])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
3,4-Difluoronitrobenzene (15.53 g, 0.098 M) was dissolved in acetonitrile (150 ml), and treated with N,N-diisopropylethylamine (31.5 g, 0.244 M) and 1,4-dioxa-8-azaspiro[4,5]decane (15.36 g, 0.107 M). The mixture was stirred and heated to reflux for 18 hours. After cooling, product precipitated as a yellow solid, and was filtered off (16.1 g); further product could be obtained by concentrating the residues (8.43 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A mixture of Compound 1 (500 mg) and phosphorus oxychloride (3.89 g) was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform and water were added and the mixture was cooled and neutralized with a 2N aqueous sodium hydroxide solution to a pH of 5 to 7. The mixture was then extracted with chloroform and the organic layer was concentrated under reduced pressure to obtain 411 mg of the desired product. When necessary, some of the product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give a purified product.
Reaction SMILES: Br[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:3].[Li]C(C)(C)C.Cl[Si:16](Cl)([CH3:18])[CH3:17].[C:20]1([CH:26]([OH:30])[CH2:27][CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(CC)CC>CCOCC.CN(C)C1C=CN=CC=1>[C:20]1([CH:26]([O:30][Si:16]([CH2:3][CH:2]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH3:18])[CH3:17])[CH2:27][CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(Br)CCCCCC
Reactant: C[Si](C)(Cl)Cl
Reactant: C=CCC(O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li]C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCC(O[Si](C)(C)CC=CCCCCC)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-octene (1.25 g, 6.6 mmol, 1.1 equiv) in Et2O (7 mL) was added dropwise t-BuLi (1.5 M, 8.8 mL, 13.2 mmol, 2.2 equiv) under a N2 atmosphere at −78° C. (internal). The pale-yellow, cloudy mixture was stirred for 1 h at −78° C. (internal). The mixture was then added to a solution of dichlorodimethylsilane (1.82 mL, 15.0 mmol, 2.5 equiv) in Et2O (10 mL) by cannula at −78° C. (internal). The mixture was allowed to warm to room temperature and was stirred for 2 h whereupon a white solid precipitated. After removal of solvent and excess dichlorodimethylsilane under reduced pressure, hexane (50 mL) was added and the solids were removed by Schlenk filtration. After removal of the solvent, the residue was dissolved in CH2Cl2 (5 mL). The solution was then added to a solution of 1-phenyl-3-buten-1-ol (888 mg, 6.0 mmol , 1.0 equiv), 4-dimethylaminopyridine (110 mg, 0.9 mmol, 0.15 equiv), and Et3N (1.25 mL, 9.0 mmol, 1.5 equiv) in C2Cl2 (10 mL) under N2 atmosphere at 0° C. (internal). The mixture was allowed to warm to room temperate and was stirred for 2 h. The mixture was then poured to ice water (20 mL) and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was removed by rotary evaporation. The residue was purified by chromatography (silica gel, hexane) followed Kugelrohr distillation under reduced pressure to afford 1.25 g (66%) of D-5 as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19]([CH2:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH:18]=[C:17]([F:30])[C:16]=1OB(O)O.C1([C@H](C)CC2C=CC(OB(O)O)=CC=2)C=CC=CC=1>>[F:14][C:15]1[CH:20]=[C:19]([CH2:21][C@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH:18]=[C:17]([F:30])[C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Cc1cc(F)c(OB(O)O)c(F)c1)c1ccccc1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: C[C@H](Cc1ccc(OB(O)O)cc1)c1ccccc1
Product: C[C@H](Cc1cc(F)c(-c2ccc(S(F)(F)(F)(F)F)cc2)c(F)c1)c1ccccc1
Yield: 42.8 %

Procedure:
A reaction was carried out in the same manner as in second step of Example 4-3 except that 3.08 g (10.9 mmol) of 4-bromophenyl sulfur pentafluoride [Br-Ph-SF5] was employed instead of 1-bromo-3,5-difluorobenzene in second step of Example 4-3 and 3.00 g (10.9 mmol) of (R)-2,6-difluoro-4-(2-phenylpropyl)phenylboric acid [H-Ph-CH(CH3)—CH2-PhFF-B(OH)2] obtained in third step of Example 4-5 was employed instead of (R)-4-(2-phenylpropyl)phenylboric acid [H-Ph-CH(CH3)—CH2-Ph-B(OH)2] to obtain 2.03 g (4.67 mmol) of (R)-4-(2,6-difluoro-4-(2-phenylpropyl)phenyl)phenyl sulfur pentafluoride [H-Ph-CH(CH3)—CH2-PhFF-Ph-SF5] (yield: 43%). MS m/e: 434(M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:15][CH:16]1[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1>O1CCOCC1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([CH2:15][N:11]3[CH2:12][CH2:13][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:10]3)[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: BrCC1CCC2(CC1)OCCO2
Reactant: COc1ccccc1C1CCNC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1COCCO1
Product: COc1ccccc1C1CCN(CC2CCC3(CC2)OCCO3)C1
Reaction time: 8 h

Procedure:
1 g of 3-(2-Methoxyphenyl)pyrrolidine is dissolved in 60 ml of dioxane and 0.85 g Nal, followed by 1.2 ml of N,N-ethyldiisopropylamine and 1.5 g of 8-bromomethyl-1.4-dioxaspiro[4.5]decane, dissolved in 5 ml of dioxane, are added. The reaction mixture is stirred overnight at 80°, evaporated and the residue extracted with ethylacetate/2N Na2CO3, followed by aqueous NaCl. The combined, dried and evaporated organic phases yields an oily residue which is purified by flash chromatography on silica gel using t-butylmethylether as a solvent system providing the product as an oil. MS (EI): M+=331; NMR (DMSO): 1.1 (2H, m), 1.45 (3H, m), 1.6-1.8 (5H, m), 2.15 (1H, m), 2.25 (2H, m), 2.4 (1H, t), 2.6 (2H, m), 2.8 (1H, t), 3.6 (1H, t), 3.75 (3H, s), 3.85 (4H, s), 6.9 (2H, dd), 7.15 (1H, t), 7.3 (1H, d).
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[CH2:21][CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:19][CH2:18]1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccc(N2CCNCC2)c(C2CCCCCC2)c1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2ccccc2C2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a mixture of the 1-(2-cycloheptylphenyl)piperazine (25 mg, 0.0967 mmol) produced in Example (44c) and tetrahydrofuran (1 mL) were added butyraldehyde (0.011 mL, 0.126 mmol), sodium triacetoxyborohydride (26.6 mg, 0.126 mmol) and acetic acid (0.011 mL, 0.183 mmol), and the mixture was stirred for 19 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 26.7 mg of 1-butyl-4-(2-cycloheptylphenyl)piperazine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:21]([C:19]1[N:20]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:23]([F:26])([F:24])[F:25])=[N:5]3)[CH2:15][CH2:14]2)[S:17][CH:18]=1)#[CH:27]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 40 °C

Procedure:
Under argon, 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-carbaldehyde (200 mg) is dissolved in methanol (5 ml) and potassium carbonate (215 mg) and dimethyl 1-diazo-2-oxopropylphosphonate (199 mg) are added. The mixture is stirred at 40° C. After aqueous work-up, the mixture is extracted with ethyl acetate and the extracts are dried with sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (67 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21]C(OCC3C=CC=CC=3)=O)[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1NC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1NC(C)=O

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185c) was dissolved in ethanol (25 mL). A 10% palladium-carbon catalyst (180 mg) was added, and the mixture was stirred in a hydrogen atmosphere overnight. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain 210 mg of the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ncnc4ccccc34)co2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). 1-Methyl-piperazine (64 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (50 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The product was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=99:01. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 4063 was obtained (35 mg, 35%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:2].[I-].[CH:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:21])[CH3:20].[CH2:41]([Li])[CH2:42]CC>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:5]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=2)[C:19]1([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:41][CH3:42]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C=Cc1cccc(C(F)(F)F)c1
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1[C@H](c2cccc(C(F)(F)F)c2)C1(C)C
Reaction time: 20 h

Procedure:
Ethyl-3-trifluoromethylcinnamate (0.98 g) (Example 2) in tetrahydrofuran under nitrogen was treated with the ylid prepared from isopropyl triphenylphosphonium iodide (2.12 g) and n-butyllithium (2.8 ml). After 20 hours at 80° the mixture was worked up in the usual manner. Purification by chromatography (silica; ether/hexane) gave (±)-n-butyl-[trans-3-(3-trifluoromethylphenyl)-2,2-dimethylcyclopropyl]-formate (0.78 g). NMR 1H: 7.22(4H,m), 4.20(2H,m), 2.72(1H,m), 2.00(1H,m), 1.40(7H,m), 0.89(6H,m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([CH:22]=O)=[N:18][CH:19]=[CH:20][CH:21]=1.[BH-](O[C:34]([CH3:36])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:20][C:19]1[C:34]([CH3:36])=[CH:15][CH:16]=[CH:17][N:18]=1)[CH2:22][C:17]1[C:16]([CH3:15])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCN(C)C(=O)OC(C)(C)C)Cc1ncccc1C

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-methyl-carbamic acid tert-butyl ester, 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave {4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester as yellow solid. 1H NMR (CDCl3) δ 1.23-1.33 (m, 2H), 1.39-1.42 (m, 11H), 2.14 (s, 6H), 2.52 (t, 2H, J=7.0 Hz), 2.72 (s, 3H), 3.00-3.06 (m, 2H), 3.73 (s, 4H), 7.09 (dd, 2H, J=7.5, 4.9 Hz), 7.39 (d, 2H, J=7.4 Hz), 8.36 (d, 2H, J=4.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:31]([C:27]5[O:26][CH:30]=[CH:29][CH:28]=5)=[O:32])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccco1
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccco1)N1CCN(c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)c[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
To a solution of {5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (150 mg, 0.40 mmol) in chloroform (10 ml) was added 4-dimethylaminopyridine (50 mg, 0.44 mmol, 1.1 equiv), followed by furan-2-carbonyl chloride (40 μl, 53 mg, 0.44 mmol, 1.1 equiv). The reaction was stirred for two days at room temperature. The reaction mixture was then diluted with dichloromethane (10 ml) and extracted with an aqueous solution of saturated sodium bicarbonate (2×10 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (20% ethyl acetate/hexanes grading to 100% ethyl acetate, then 10% methanol/dichloromethane) provided the desired product (110 mg, 59%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1O.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].[OH-:19].[K+]>C1C=CC=CC=1.CCCCCC>[CH3:14][C:15]12[CH2:8][CH:3]3[CH:2]([C:1]([CH3:10])=[CH:6]1)[C:17]([CH3:18])([CH2:7][CH2:5][CH2:4]3)[C:16]2=[O:19]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: [OH-]
Reactant: C=CCCCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC1=CC2(C)CC3CCCC(C)(C2=O)C13

Procedure:
6.8 g. of mesitol dissolved in 50 ml of benzene are treated with 2.4 g of sodium hydride (50 percent suspension in oil). After completion of the salt-formation, 8.5 g of 5-bromo-1-pentene are added thereto. The reaction mixture is heated at reflux for 24 hours, taken up in hexane and shaken with an aqueous potassium hydroxide solution (10 percent by weight) and Claisen's alkali (35 g of KOH, 25 ml of water and 100 ml of methanol). The organic phase is dried, evaporated and chromatographed on silicagel using hexane and 3 percent diethylether in hexane as the elution agent. Evaporation of the eluate and recrystallization of the residue from hexane yields 1,3,9-trimethyl-tricyclo [5,3,1,03,8 ] undeca-9-en-2-one of melting point 46° -47°C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24]CCl>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylic acid (26a) (0.26 g, 0.79 mmol) in dichloromethane (3.5 ml) oxalyl chloride (0.21 ml, 2.37 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.27 g, 98%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:11][S:10][C:4]1[N:5]=[CH:6][C:7]([C:8]#[N:9])=[CH:2][N:3]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1ncc(C#N)cn1
Reaction time: 3 h

Procedure:
To a stirred mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.843 g, 4.54 mmol) and zinc dust (1.48 g, 22.71 mmol) in ethanol (7.5 mL) and water (1.4 mL) was slowly added acetic acid (0.29 mL, 5.13 mmol). The resulting reaction mixture was vigorously stirred for 3 h. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel 60 (35 g), eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 152.