Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][C@@H:15]2[CH2:37]O)=[O:13])=[CH:7][CH:6]=1.S(Cl)(C)(=O)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C(Cl)Cl>[C:33]([Si:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[O:19][C@@H:17]1[CH2:18][N:14]2[C:12](=[O:13])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:40])([F:39])[F:1])=[CH:10][CH:9]=3)[CH2:37][C@H:15]2[CH2:16]1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H](CO)N(C(=O)Nc2ccc(OCC(F)(F)F)cc2)C1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H]1C[C@@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2R,4S)-4-(tert-Butyl-diphenyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid [4-(2,2,2-trifluoro-ethoxy)-phenyl]-amide (400 mg, 0.699 mmol) in DCM (5 mL) was added TEA (0.14 mL, 1.048 mmol) followed by mesylchloride (0.07 mL, 1.048 mmol) at 0° C. and stirred at room temperature for 12 h. DCM was added, the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. 400 mg of the residue was taken up in THF (5 mL), t-BuOK (91 mg, 0.813 mmol) was added and the mixture was stirred for 1 h at room temperature. NH4Cl aq. and DCM was added. The organic layer was washed with water and brine, dried over Na2SO4. The residue was purified through column chromatography over silica (elution with 10% ethyl acetate in hexane) to afford (6S,7aR)-6-(tert-Butyl-diphenyl-silanyloxy)-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one as an off white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCNCC1
Reactant: ClCCN1CCCCC1
Product: O=C1CCN(CCN2CCCCC2)CC1

Procedure:
1-(2-(1-Piperidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and 1-(2-chloroethyl)piperidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.I[CH:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH3:10]>CC(CC)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CCCCC(C)I
Solvent: CCC(C)=O
Product: CCCCCCN1CCC(O)CC1
Yield: 63.9 %

Procedure:
4-Hydroxypiperidine (2.02 g, 20 mmol) was dissolved in 100 mL of methyl ethylketone. To this stirred mixture was added 2-iodohexane (1.5 mL, 10 mmol) and the resulting solution was heated at reflux for 1.5 hours. The mixture was allowed to cool and was then washed with saturated aqueous sodium bicarbonate (3×75 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated, and the residue was dried overnight under house vacuum to yield 1.184 g (64%) of the title compound which was used without further purification. 1H NMR consistent with desired product. MS(FD) 186(M+).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
A mixture of methyl 2-(2-nitro-4-trifluoromethylphenoxy)benzoate (26 g, 0.076 mol) and 10% palladium on carbon (1 g) in ethyl acetate (400 mL) was hydrogenated in a parr bottle at 55 psi for 2 h. The reaction mixture was flushed with argon, filtered through Celite® and evaporated. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ7.91 (dd, 1H), 7.45-7.53 (m, 1H), 7.17-7.24 (m, 1H), 6.88-7.03 (m, 3H), 6.78 (d, 1H), 4.25 (br s, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccn3C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cccn3C)nc2c1C#N
Temperature: 110 °C
Yield: 26.9 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (53 μl, 0.42 mmol) and triethylamine (100 μl) were added to a dimethyl sulfoxide (2 ml) solution of 7-fluoro-5-methyl-2-(1-methyl-1H-pyrrol-2-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-166) (69 mg, 0.21 mmol). The system was purged with nitrogen, then sealed up, and heated at 110° C. for 3.5 hours. After cooling, the solvent was evaporated away under reduced pressure, the resulting residue was dissolved in chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was separated and purified by preparative TLC to obtain a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (24 mg, 27%) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].[N+:26]([C:29]1[CH:30]=[C:31]2[C:36](=O)[O:35][C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1)([O-:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)(=O)C>[N+:26]([C:29]1[CH:30]=[C:31]2[C:32](=[CH:38][CH:39]=1)[C:33](=[O:34])[N:2]([C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10])[C:36]2=[O:35])([O-:28])=[O:27]
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Temperature: 130 °C
Reaction time: 6 h
Yield: 81.9 %

Procedure:
To a suspension of 4 (0.4 g, 1.08 mmol), 4-nitrophthalic anhydride (0.259 g, 1.34 mmol), and sodium acetate (0.125 g, 1.45 mmol) was added acetic acid (4 mL) and the resulting mixture was stirred at 130° C. After 6 h, the mixture was quenched with sodium bicarbonate and extracted with DCM. The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 9 (0.45 g, 87%). Rf=0.36 (95:5 DCM:MeOH). 1H NMR (400 MHz, CDCl3) δ 8.62 (par obsc s, 1H), 8.60-8.51 (par obsc m, 1H), 8.16-7.86 (m, 2H), 7.44-7.27 (m, 5H), 5.07 (m, 2H), 3.23 (m, 3H), 2.93-2.49 (m, 3H), 2.46-2.23 (m, 1H), 2.14 (m, 1H), 1.79-1.47 (m, 3H), 1.45-1.17 (m, 2H), 1.00-0.75 (m, 1H). MS (ESI) m/z calcd for C25H25N4O8 [M+H]+ 509.5, found 509.3.
Reaction SMILES: [H][H].[CH:3]1([P:9]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([S:17]([O-:20])(=[O:19])=[O:18])[CH2:12]2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:27].C1(P(C2CCCCC2)(C2CCCC(S(OCC)(=O)=O)C2)=O)CCCCC1>CO>[C:21]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:11]2[CH:12]=[C:13]([S:17]([O-:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[Na+:27]
Reactant: [H][H]
Reactant: O=P(C1CCCCC1)(C1CCCCC1)C1CCCC(S(=O)(=O)[O-])C1
Agent: CCOS(=O)(=O)C1CCCC(P(=O)(C2CCCCC2)C2CCCCC2)C1
Agent: [Na+]
Solvent: CO
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc(S(=O)(=O)[O-])c1

Procedure:
DPPOBS-Na (7.0 g; 18.4 mmoL), prepared as above, is dissolved in dry methanol (70 mL) and placed into a Parr reactor (150 mL) containing 7 g of catalyst comprising Ru (5 wt percent) on carbon. Hydrogenation is carried out at 1,000 psi (6,895 kPa) hydrogen and at 100° C. The reaction is monitored by 31P and 1H NMR. After 2 weeks, resonances for the aromatic protons in the 1H NMR spectrum disappear, and new resonances appear in the 31P NMR spectrum. The mixture is filtered; a black solid on the filter is washed with methanol. The solvent is evaporated, and the residue is dried in vacuum to give a white solid identified as sodium 3-(dicyclohexylphosphinyl)cyclohexane-1-sulfonate (DCHPOCHS-Na). Yield 4.0 g (55%). 31P{1H} NMR (CD3OD, ppm): 5.68 (major, ca. 87%) and 57.99 (minor, ca. 13%). (3) Step 3 of Example 1 is repeated using the intermediate product from step (2) of this example. Subsequently, steps 4 to 6 of Example 1 are also reproduced to yield Ligand 1 of this invention, namely, the sodium salt of 3-(dicyclohexylphosphino)cyclohexane-1-sulfonic acid.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:11]2([CH2:16][CH2:15][C:14]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:14]2([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:12][C:11]3([CH2:31][CH2:32][NH:8][CH2:9][CH2:10]3)[CH2:16][CH2:15]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(OCCN1CCCC1)(c1cccnc1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Pyridin-3-yl-3-(2-pyrrolidin-1-yl-ethoxy)-9-azaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (0.282 mmol, 1 equiv.) was dissolved in DCM (3 ml). At 0° C., trifluoroacetic acid (1.5 ml) was added, and the mixture was stirred for 2 hours at 25° C. The solvent was concentrated under reduced pressure and the residue was taken up in DCM (2×10 ml) and dried to yield the desired product.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:1]([CH2:9][C:10]([OH:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
To 11.6 g (60.3 mmol) of ethyl benzoylacetate, was added 60 mL of a 1 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 16 hours. After removing organic substances by ether, the reaction solution was acidified by adding concentrated hydrochloric acid while cooling the solution in an ice bath to give a precipitate. The precipitate was collected by filtration, washed with cold water, and dried under reduced pressure. As a result, 6.56 g (40.0 mmol, 66.3%) of benzoylacetic acid was obtained as a pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=[O:24])=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C.O>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([NH:7][C:6]4[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[O:24])[CH:18]=3)[NH:14][N:15]=2)=[CH:31][CH:30]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing 3-nitroaniline (96 mg, 0.694 mmol) in pyridine (5 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.631 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. Water (30 mL) was then added and the resulting precipitate was filtered and dried to afford the title compound. This precipitate was taken on directly to the next step for deprotection.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][C:26]([CH:35]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:35][C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: Cc1cccc(N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c1C
Yield: 72.9 %

Procedure:
Compound 20 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH2:22][C:23](N(OC)C)=[O:24])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([CH3:13])=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H](N(CC(=O)C(C)=C)C(=O)OC(C)(C)C)C=C)([C:32](C)([CH3:34])[CH3:33])(C)C.C([Mg]Br)=CC(=C)C>>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH2:22][C:23](=[O:24])[C:32]([CH3:34])=[CH2:33])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:11]([CH3:13])=[CH2:12])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C)C(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: C=C(C)C=C[Mg]Br
Product: C=C(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(=C)C
Yield: 92 %

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 188, 4.24 g, 10.18 mmol) following the procedure described for Intermediate 6 substituting the relevant isoprenyl magnesium bromide (0.5 M in THF) (204 mL, 101.77 mmol). Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a light yellow oil (3.72 g, 92%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11])=[O:22]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a mixture of (1R,2S)-1-amino-2-indanol (500 mg, 3.35 mmol) and triethylamine (0.51 mL, 3.69 mmol) in anhydrous CH2Cl2 at 0° C. was added chloroacetyl chloride (0.295 mL, 3.69 mmol) dropwise. The resulting mixture was stirred for 30 min, quenched with saturated aqueous NaHCO3 (15 mL) and then extracted with EtOAc (2×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc 70:30 to 0:100, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: ClCCNCCCl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A stirred mixture of bis-(2-chloroethyl)amine hydrochloride (5.35 g, 30.00 mmol), 4-aminobenzoic acid ethyl ester (4.13 g, 25.00 mmol), and potassium carbonate (4.40 g, 32.00 mmol) in chlorobenzene (200 mL) was refluxed for 30 hours. After cooling to ambient temperature the mixture was filtered and the filtrate was concentrated in vacuo to dryness to provide 4.27 g (73% yield) of 4-piperazin-1-yl-benzoic acid ethyl ester.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])([C:34](OC)=[O:35])[C:30](OC)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])([CH2:34][OH:35])[CH2:30][OH:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CCCCC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(C(=O)OC)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCCCC(CO)(CO)CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of dimethyl 2-[2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-2-pent-4-enylmalonate (910 mg) in diethyl ether (15 mL) was added lithium aluminum hydride (117 mg) under ice cooling. After stirring the solution at room temperature for 1 hour, water (0.12 mL) and a 15% aqueous sodium hydroxide solution (0.12 mL) were successively added thereto. The solution was stirred at room temperature for 15 minutes. Water (0.36 mL) was then added and the solution was stirred at room temperature for additional 15 minutes. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=6:4) to give the title compound (640 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li]C.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH:22]=[O:23]
Reactant: COCOc1ccc(OC)cc1
Reactant: O=CN1CCCCC1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(OC)c(C=O)c1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzene (20 g, 0.1 2 mol) in THF is added diisopropylamine (0.24 g, 2.4 mmol). The solution is cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture is warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture is quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature is then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture is adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer is combined, dried over Na2SO4, and concentrated. The residue is purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)benzaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccccn3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccn1)c1ccccc1-2
Yield: 49.7 %

Procedure:
The procedure is performed as in Example 21, but starting with 0.7 g of 10-(2-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 200 ml of dimethylformamide, 5 ml of acetic acid and 70 mg of 10% palladium on charcoal. The crude product (1.1 g) is purified by trituration in a mixture of 10 ml of dichloromethane and 40 ml of ethyl ether, followed by crystallization in 25 ml of dimethylformamide and 40 ml of water. 0.35 g of 10-(2-pyridylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a light beige solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.5, H: 4.6, N: 17.9, O: 5.5).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[C:11]=1[CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([CH:23]=[CH2:24])=[CH2:22]>>[C:1]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[C:12]([CH3:17])[C:11]=1[CH3:18])[O:16][C:21]([O:20][CH3:19])([CH3:22])[CH2:23][CH2:24]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=C)OC
Reactant: Cc1c(O)ccc(OC(=O)c2ccccc2)c1C
Product: COC1(C)CCc2cc(OC(=O)c3ccccc3)c(C)c(C)c2O1

Procedure:
By the manner of Example 45, 4-benzoyloxy-2,3-dimethylphenol was reacted with 2-methoxybutadiene to give (±)-6-benzoyloxy-2-methoxy-2,7,8-trimethylchroman as a white powder, m.p. 101.5°-102.5°, from ether-30°-60° petroleum ether.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:11]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)[CH2:12][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc(C=CC(=O)O)cc1
Reaction time: 10 h
Yield: 78 %

Procedure:
In 50 ml of dimethyl sulfoxide was suspended 15.5 g of 4-hydroxycinnamic acid, 30.0 g of bromoheptyl and 50.0 g of potassium carbonate, and were vigorously stirred for 10 hours with a mechanical stirrer while the flask was heated in oil bath under reflux. After the obtained reaction mixture was cooled, it was filtered through Celite, and the resultant residue was washed with 300 of ethyl acetate. After 500 ml of water was added to the washed mixture and the mixture was extracted with 2.5 liter of ethyl acetate, the obtained extract (organic layer) was concentrated by removing the solvent in vacuo. To the resultant residue was added 100 ml of ethanol, an aqueous solution (20 ml) containing sodium hydroxide of 10 g was added and stirred at 80° C. for 1 hour. After the resultant reaction mixture was cooled, the precipitated crystals were filtered in vacuo, and the residue was washed with 100 ml of ethanol. The washed residue was placed in 300 of dilute hydrochloric acid of 40° C., and stirred for 1 hour. The reaction mixture was filtered in vacuo and dried to obtain the above compound (e) of 19.1 g (yield: 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23].[BH4-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][NH:17][C:16]2=[O:23]
Reactant: COc1ccc(OC)c(CCc2ccc3nc[nH]c(=O)c3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(OC)c(CCc2ccc3c(c2)C(=O)NCN3)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
130 g of 6-[2-(2,5-dimethoxyphenyl)ethyl]-3H-quinazolin-4-one are dissolved in 3 ml of acetic acid and treated with 58 mg of sodium borohydride. After stirring for 5 hours at room temperature, the mixture is poured onto 2 M aqueous pH7 buffer solution and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel to give the title compound as colourless crystals. mp.: 138-140°.