Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH2:10][CH2:11]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:8][CH2:9]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C3(C)OCCO3)CC2)cc1
Solvent: CN(C)C=O
Product: CC1(C2(CCSc3ccccc3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
590 mg of 10 is dissolved in 2 ml of dimethylformamide (DMF) and added under nitrogen to a mixture of 300 mg of potassium-t-butylate and 0.27 ml of thiophenol in 5 ml of DMF. It is stirred for 1 hour at room temperature and then quenched with sodium chloride solution. It is extracted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 630 mg of title compound 11 accumulates as a yellowish oil.
Reaction SMILES: C(OCC)(=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:21][C:22](=[O:32])[CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25](O)=O)(C)(C)C>C1COCC1>[CH2:28]([CH:24]1[CH2:25][O:32][C:22](=[O:21])[CH2:23]1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
Ethyl acetate (0.12 mL, 1.22 mmol) in THF (2 mL) was added dropwise to a stirring solution of lithium bis(trimethylsilyl)amide (1.22 mL of a 1 M solution in THF, 1.22 mmol) at −78° C. under argon. After 20 minutes, 3 (0.21 g, 1.16 mmol) in THF (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (3 mL) and allowed to warm to room temperature. The mixture was diluted with ether (20 mL) and dilute hydrochloric acid (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with ether (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 99:1) to give the nitro-ester 4 (0.13 g, 41%) as a colorless liquid; Rf(heptane/ethyl acetate, 9:1) 0.32; νmax(film)/cm−1 1731 (C═O), 1547 (NO2), 1375 (NO2); δH (400 MHz; CDCl3): 4.73 (2H, s, CH2NO2), 4.14 (2H, q, J=7.1, CO2CH2Me), 2.58 (2H, s, CH2CO2Et), 2.07 (2H, m), 1.71–1.66 (4H, m), 1.60–1.24 (8H, m), 1.26 (3H, t, J=7.2, CO2CH2Me); m/z (ES+) 270 (M+H, 100%).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[NH2:21][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: CC(Oc1ncn(-c2cccc(F)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(Oc1ncn(-c2cccc(F)c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Two g of the product of Example 58 was dissolved in 10 ml of dimethylformamide and 1.9 g of carbonyldiimidazole was added. The mixture was stirred at room temperature for 20 minutes, and 0.6 g of 35% ammonium hydroxide was added. The mixture was then stirred for 20 hours at room temperature and was poured over ice-water. The product was collected by filtration and dried to obtain 1.4 g of the desired product, m.p. 156°-158°.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[Si:25]([O:32][CH2:33][CH:34]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([BH3-])#N.[Na+].O>CO>[Si:25]([O:32][CH2:33][CH2:34][N:16]1[CH2:17][CH2:18][CH:14]([CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([I:2])=[CH:12][CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)[CH2:15]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(CCO[Si](C)(C)C(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then (tert-butyldimethylsilyloxy)acetaldehyde (1 mL, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column eluting with 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 253 mg (39% yield) of ethyl 1-((1-(2-(tert-butyldimethylsilyloxy)ethyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[C@H:28]([CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C2CC2)c1
Yield: 98.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (962 mg) described in Preparation Example 109 and (R)-4-methyloxazolidin-2-one (354 mg) described in Preparation Example 25, the title compound (990 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(C2CCN(C(=O)OC(C)(C)C)C2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To a stirred solution of tert-butyl 3-(5-methylpyridin-2-yl)pyrrolidine-1-carboxylate (260 mg, 1.0 mmol) in dry CH2Cl2 (3 mL) was added TFA (2 mL, 20% in CH2Cl2) dropwise at 0° C. The reaction mixture was stirred at rt for 3 h. TLC showed the disappearance of starting material. The reaction mixture was concentrated under vacuum to afford crude 5-methyl-2-(pyrrolidin-3-yl)pyridine (170 mg, 96%), which was used for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][S:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][S:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cscc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.6 %

Procedure:
A solution of 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (200 mg, 620 μmol, 1.0 eq.) in EtOAc (25 mL) was combined with Pd(OH)2/C (70 mg) under hydrogen (1 atm). MeOH (10 mL) was added and the resulting solution was stirred for 20 hours at room temperature. The solution was then stirred for an additional 16 hours while the temperature was maintained at 40° C. in an oil bath. The solids were filtered and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 4-(4-methoxycarbonylthiophen-3-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc2c(cn1)[nH]c1ccccc12
Solvent: ClCCl
Product: CS(=O)Cc1cc2c(cn1)[nH]c1ccccc12

Procedure:
160 mg of 3-methylthiomethyl-β-carboline are stirred in 15 ml of methylene chloride with 163 mg of m-chloroperbenzoic acid for 3 hours at room temperature. After extraction with semiconcentrated sodium bicarbonate solution, the organic phase is dried, filtered and concentrated. The residue is stirred with ethyl acetate/ethanol. 76 mg of 3-methylsulfinylmethyl-β-carboline with a 175°-178° C. melting point are obtained as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])[CH3:2].[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=2)[C:7]=1[CH3:16])[CH3:2]
Reactant: ClCc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2cccc(OCc3ccccc3)c2)c2ccc(Br)cc12
Yield: 60.1 %

Procedure:
1-[(3-Benzyloxyphenyl)methyl]-5-bromo-2-methyl-1-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1, Part F, 592 mg (2 mmol) of 5-bromo-2-methyl-1H-indole-3-acetic acid ethyl ester (Example 51, Part A) was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 465 mg (2 mmol) of 3-benzyloxybenzylchloride and after workup of the reaction mixture and chromatograpy on silica(eluted with 33% EtOAc/hexane) there was obtained 592 mg (60%) of 1-[(3-benzyloxyphenyl)methyl]-5-bromo-2-methyl-1H-indole-3-acetic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-hydroxy-cyclopentanecarboxylic acid methyl ester (1.6 g, 1.0 eq, cis/trans-mixture from step 1) in dichloromethane (25 mL) was cooled to −20° C. and treated with triethylamine (1.4 g, 1.3 eq) and methansulfonyl chloride (1.5 g, 1.2 eq). The mixture was stirred at −20° C. for 20 min and then partitioned between water and dichloromethane. The organic phase was washed with brine, dried over sodium sulfate and evaporated. The title compound was obtained as a yellow liquid (2.4 g, 97%) and was used crude in the next step.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH2:36][OH:37])=[CH:34][C:33]2[C:28](=[C:29]([CH3:38])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:10]1[C:2]([O:37][CH2:36][C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:38])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3Cl)nc12
Reactant: Clc1ncnc2nc[nH]c12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2cc(COc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared according to procedure L A mixture of 6-chloropurine (75 mg, 0.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (109 mg, 0.97 mmol) in DMSO (0.5 mL) was stirred at rt for 5 h and was then added via cannula to a mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)-methanol (69 mg, 0.24 mmol) and sodium hydride, 60% dispersion in mineral oil (39 mg, 0.97 mmol) in DMSO (0.5 mL) that had been stirred at rt for 15 min prior to the addition. The mixture was stirred at rt for 3.5 h, cooled to 0° C., and H2O (5 mL) was added carefully. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel (deactivated with 2M NH3 in MeOH), and purified by flash chromatography (Biotage® Si 25+M) eluting with 2M NH3 in MeOH/CH2Cl2 (5%) to provide a white solid [PI3Kδ IC50=25 nM]. MS (ESI+) m/z=402.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[C@H:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Product: O=C(O)C[C@@H]1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 67.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 56 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (13 mg, 70%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Product: NC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 3373 %

Procedure:
A mixture of morpholine (2.0 g, 0.23 mmol) and 4-fluorobenzamide (1.2 g, 8.6 mmol) is heated at 120° C. The conversion of the 4-fluorobenzoamide is complete after 10 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 1.6 g of the title-compound. Yield: 94%; m.p. 220-221° C.; MS 206 (100, M+); H1 NMR (DMSO): δ 7.76 (d, 2H), 7.75 (b, 1H), 7.05 (b, 1H), 6.94 (d, 21H), 3.73 (t, 4H), 3.20 (t, 4H); C13 NMR (CDCl3): δ 167.61, 152.90, 128.79, 123.93, 113.31, 65.92, 47.36.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1>CO>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (64 mg), acetic acid (0.044 mL) and sodium acetate (62.6 mg) in methanol (10.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (120 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (97 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-4-piperidinecarboxylate (D81) (160 mg). The crude product was used for next step without further purification. MS (ES): C30H35F3N2O3S requires 560. found 561.3 (M+H+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:12]=[C:11]1[NH:6][CH2:7][CH:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(C(=O)O)CN1
Temperature: 80 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
To an optically active compound of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (1.36 g) were added anisole (758 μl) and trifluoroacetic acid (10 ml), and the mixture was stirred at 80° C. for 6 hours. This reaction solution was cooled to room temperature, and then concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (628 mg).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][C:10](=[O:12])[CH3:11])[CH3:8].O1CCCC1.CC[Al-]CC.[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][CH:10]([OH:12])[CH3:11])[CH3:8]
Reactant: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Agent: CC[Al-]CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=CC(C)O)c1ccccc1-c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of 1.6 g. 2-(p-biphenylyl)-2-penten-4-one in 25 ml. of dry tetrahydrofuran, at 0° C., 10 ml. of a solution of 25% (W/W) of sodium aluminum diethyl dihydride in toluene is dropwise added. After 20 minutes at 0° C., the mixture is poured onto ice and extracted with chloroform. Evaporation of the chloroform gives 2-(p-biphenylyl)-2-penten-4-ol, m.p. 137°-138° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](#[N:24])[CH3:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[CH2:23][C:22]#[N:24])[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCCCCOCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(4-benzyloxybutoxy)benzaldehyde gave 3-[3-(4-benzyloxy-butoxy)-phenyl]-3-hydroxypropionitrile as yellow oil. Yield (0.3 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.37 (m, 4H), 7.27-7.32 (m, 2H), 6.93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.4 Hz, 2H), 4.52 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H), 1.87-1.94 (m, 2H), 1.77-1.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH2:20])=[N:6][CH:7]=1.[CH3:22][S:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([S:23][CH3:22])=[CH:25][C:26]=2[O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2ccc(SC)cc2OCCCNC(=O)OC(C)(C)C)c1
Yield: 50 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-aminobenzamide and 4-(methylthio)-2-(3-(t-butoxycarbonylamino)-propoxy)benzoic acid gave the title compound as a white solid (12 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:34]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[N:10]2[CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35][CH2:34]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 18.5 %

Procedure:
7-Methoxy-3-methylquinazoline-2,4(1H,3H)-dione (Intermediate 112, 523 mg, 2.5 mmol) was deprotonated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 200 mg (18%) of the product as a colorless solid.
Reaction SMILES: COC1C=C2C[CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])C2=CC=1OC.C(O)(=O)CC(O)=[O:32]>>[N:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:13][C:11]([OH:12])=[O:32])=[CH:17][CH:18]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Product: O=C(O)C=Cc1ccncc1

Procedure:
Patent application WO 97/22584 describes the preparation of Donepezil by reaction of pyridine-4-carboxyaldehyde with malonic acid to give 3-(pyridin-4-yl)-2-propenoic acid, followed by hydrogenation of the double bond to give 3-(piperidin-4-yl)-2-propionic acid. Reaction of this intermediate with methyl chloroformate afforded 3-[N-(methyloxycarbonyl) piperidin-4-yl]propionic acid. This was followed by reaction with oxalyl chloride to give methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate. Reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. Reaction with tetramethyldiaminomethane afforded 4-[2-(3,4-dimethoxybenzoyl)allyl] piperidin-1-carboxylate. Reaction with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-yl)methylpiperidin-1-carboxylate. This was followed by treatment with base to give 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one, then reaction with benzyl bromide afforded Donepezil (Scheme 3).