Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[CH:5]=[CH:4][C:3]=1[CH3:15].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(N)nc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To N-(6-chloro-5-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (4.00 g, 17.7 mmol) was added 6 N HCl (20 mL) at room temperature. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was basified with drop-wise addition of sat. NaHCO3 to pH 8-9, and then the mixture was extracted with CH2Cl2 (3×). The organic phases were dried over Na2SO4 and evaporated under vacuum to obtain the 6-chloro-5-methyl-pyridin-2-ylamine (900 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 4.39 (br s, 2H), 2.22 (s, 3H). MS (ESI) m/z: 143 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15](OC)=[O:16])[CH:11]=2)=[N:6][CH:7]=1.[NH3:26]>>[Br:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15](=[O:16])[NH2:26])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Reactant: N
Product: Cc1cc(Nc2nc(NCc3cc(C(N)=O)no3)ncc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
5-Bromo-2-[3-(methoxycarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 104; 50 mg, 0.11 mmol) was suspended in 7N methanolic ammonia (5 ml) and stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was triturated with DCM/diethyl ether (50:50) and the product collected by filtration to give the title compound (35 mg, 76%). NMR (DMSO): 2.18 (s, 3H), 4.57 (d, 2H), 6.28 (br s, 1H), 6.50 (s, 1H), 7.72 (s, 2H), 8.01 (s, 1H), 8.05 (s, 1H), 12.06 (s, 1H); m/z 393 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=[CH2:13]>C(#N)C.[I-].[Na+]>[Cl:10][CH2:11][C:12]([CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH2:13]
Reactant: C=C(CCl)CCl
Reactant: [O-]c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(CCl)COc1ccc(Cl)cc1
Yield: 54 %

Procedure:
0.5 mol of sodium 4-chlorophenolate in acetonitrile are added dropwise to a solution of 125 g (1 mol) of 3-chloro-2-chloromethylpropene in 50 ml of acetonitrile. After addition of 0.5 g of sodium iodide, the reaction mixture is heated under reflux for 12 hours and is then filtered cold. The filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride and the solution is washed with water, dried over sodium sulphate and concentrated. 58.6 g of about 60% pure 2-chloromethyl-3-(4-chlorophenoxy)-propene are obtained and are dissolved in 500 ml of methylene chloride, and 43 g (0.25 mol) of 3-chloroperbenzoic acid are added.
Reaction SMILES: [O:1]=[C:2]([C:16]1[S:23][C:22]([CH3:24])=[C:21]2[C:17]=1[CH2:18][C@H:19]1[C:25]([CH3:27])([CH3:26])[C@H:20]12)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1>C(O)C.[Pd]>[O:1]=[C:2]([C:16]1[S:23][C:22]([CH3:24])=[C:21]2[C:17]=1[CH2:18][C@H:19]1[C:25]([CH3:27])([CH3:26])[C@H:20]12)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1sc(C(=O)C=Cc2ccc(CCC(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1sc(C(=O)CCc2ccc(CCC(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-phenyl}-propionic acid (121 mg, 0.32 mmol), Pd/C (40 mg, 10% Pd) in ethanol (8 mL) is stirred at rt under 1 bar H2. The reaction mixture is filtered, the filtrate is evaporated to give 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-propionic acid (120 mg) as a pale yellow oil; LC-MS: tR=1.07 min, [M+1]+=383.17.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.Cl>CC(C)=O.CN(C)C=O>[O:23]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:18][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: BrCC1CCCO1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Nc1nc(N)c2c(ccc3c2ccn3CC2CCCO2)n1
Reaction time: 24 h

Procedure:
In a manner similar to that of Example 2, 3.98 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in ca. 260 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 3.63 g. tetrahydrofurfuryl bromide. After stirring the mixture at ca. 25° for 24 hours, 0.21 g. ca. 50% sodium hydride-mineral oil dispersion are added. Stirring is continued for one-hour, 0.73 g. tetrahydrofurfuryl bromide is added, and, after stirring for 6 hours, the reaction mixture is kept at ca. 25° for ca. 70 hours. Processing of the reaction mixture in the manner described in Example 2 (Method A) yields a brown gum which is dissolved in 40 ml. N hydrochloric acid. Dilution of the aqueous acidic solution with 40 ml. acetone gives crystals that are collected and twice recrystallized from methanol-acetone to yield 1.20 g. title compound as a monohydrochloride salt bearing one-third molecule of water per molecule of diamine salt, m.p. 310°-311° (dec.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35]C)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:29]([O:28][C:26]([N:24]1[CH2:25][C@@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][CH:7]=2)=[O:18])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:21][C@@H:22]([C:33]([OH:35])=[O:34])[CH2:23]1)=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1,3-dicarboxylate (1.08 g) was dissolved in methanol (25 ml) and THF (12 ml), 2 M aqueous sodium hydroxide solution (4.79 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (1.05 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O.ClC1C=CC([N+]([O-])=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: OCCO
Product: Nc1ccc(OCCO)cc1

Procedure:
2-(4-Aminophenoxy)ethanol was prepared, using the method described in Example C3, by the reduction of 2-(4-nitrophenoxy)ethanol which was prepared by heating a mixture of 4-chloronitrobenzene, ethylene glycol and sodium carbonate in a sealed vessel (Beil. 6, II, 222).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]NC2N=C(NCCC3C=CC(OC)=C(OC)C=3)C=CN=2)=[CH:12][CH:11]=1.COC1C=C(CCNC2C=CN=C(NCC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC.[O:68]=[C:69]1[NH:73][C:72](=[O:74])[CH:71](CC2C=CC(C(O)=O)=CC=2)[S:70]1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:71]2[S:70][C:69](=[O:68])[NH:73][C:72]2=[O:74])=[CH:14][CH:15]=1
Reactant: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)cc1OC
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)O)cc2)S1
Agent: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Product: Nc1ccccc1NC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Yield: 51 %

Procedure:
Following the procedure described for the synthesis of compound 10a (scheme 2, Example 2) but replacing acid 9 by the acid 352, title compound was obtained in 51% yield. 1H NMR: (400 MHz, DMSO-d6, δ (ppm): 12.04 (br s, 1H), 9.62 (s, 1H), 7.90 (d, j=8.2 Hz, 2H), 7.36 (d, J=8.2, 2H), 7.16 (d (dd) J=8.4, 1H), 7.13 (d (dd), J=6.7, 1H), 6.95 (dd, J=1.6 Hz, J=7.8 Hz, 1H), 6.75 (dd, j=1.4 Hz, j=8.0 Hz, 1H), 6.57 (dd, j=1.4 Hz, 7.6 Hz, 1H), 4.99 (dd, J=4.7 Hz, J=9.0 Hz, 1H), 4.96 (br s, 2H), 3.45 (dd, J=4.5 Hz, J=14.1 Hz, 1H), 3.22 (dd, J=9.0 Hz, J=14.3 Hz, 1H). LRMS: 341.3 (calcd.), 342.3 [MH]+ (found).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C(O)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: O=Cc1cccs1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)sc(N=Cc2cccs2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.5 %

Procedure:
In a 250 mL flask comprising 50 ml absolute ethanol, was dissolved 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester (470 mg, 5.0 mmol) followed by 2-thiophene carboxaldehyde (646 mg, 2.5 mmol). After the addition of one drop of acetic acid, the solution was stirred at room temperature for 4 days. The solvent was then removed from the resulting orange solution and the residue was purified by flash chromatography (SiO2) using 20% ethyl acetate/hexane to afford the title compound as a yellow solid (454 mg, 52%). M.p.=145°-147° C. 1H-NMR (200 MHz, [D] chloroform): δ=9.94 (s, 1H), 8.06 (s, 1H), 7.20 (t, 1H), 7.18 (d, 1H), 7.12 (m, 1H), 7.02 (m, 1H), 4.41 (t, 2H), 4.24 (q, 2H), 1.48 (t, 3H), 1.29 (t, 3H). 13C-NMR (50 MHz, [D] chloroform): δ=164.5, 159.9, 145.9, 142.7, 134.0, 131.2, 130.2, 127.9, 102.9, 61.6, 60.3, 14.5, 14.3. FAB-MS: m/z 351.8 ([M]+, 100%). Anal. calc. for C15H16N2O4S2 (352.06): C, 51.12, H, 4.58, N, 7.95, O, 18.16, S, 18.20 found: C, 51.21; H, 4.63; N, 7.77, S, 17.81. λmax (DMSO)=402 nm. ε (DMSO)=3.6×104 M−1 dm−1; λmax (acetonitrile)=408 nm, λfl(acetonitrile)=604 nm.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C.[BH4-].[Na+]>CO>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CNc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxyaniline (10 mmol) and 4-nitrobenzaldehyde (10 mmol) in methanol is stirred at ambient temperature for 18 hours. The precipitate obtained is filtered off and washed and then dissolved in tetrahydrofuran. After the addition of acetic acid and sodium borohydride (25 mmol), the reaction mixture is stirred at ambient temperature for 1 hour, then the solvent is evaporated off and the crude residue is purified by chromatography on silica using dichloromethane as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH:24]=[O:25].[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH2:24][OH:25]
Reactant: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCOCOc1c(C/C=C(\C)CO)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To a solution of (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enaldehyde (4.6 g) in methanol (60 ml) was added sodium borohydride (0.528 g). After one hour the reaction was added to water (250 ml) and extracted with ethyl acetate (2×150 ml). The extract was dried and evaporated to give (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-en-1-ol.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=CCCCCC(=O)O
Yield: 40.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 1 g of p-toluene sulfonic acid were refluxed for 8 hours, the methanol formed being distilled off constantly. Fractional distillation under reduced pressure gave 13.3 g (yield 41% of theory) of 5-formylvaleric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)O

Procedure:
To a stirred solution of methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)benzoate from Step 2 above (2.26 g, 6.43 mmol) in methanol (25 mL) was added 2N NaOH (16 mL, 32.2 mmol). The reaction mixture was refluxed for 30 minutes and cooled in a ice water bath. The solution was acidified with 5% citric acid, then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (2×75 mL). The organic layer was dried (MgSO4), filtered, then the solvent was evaporated to give 2-methoxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)benzoic acid as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH3:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccn(N)c1C(=O)Nc1ccccc1
Product: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Yield: 23 %

Procedure:
Prepared from 2.00 g (9.29 mmol) of 1-amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide and 2.11 g (11.15 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid following the experimental procedure described in Preparation 22a. After purification by flash chromatography (0 to 10% methanol in dichloromethane), 825 mg (23% yield) of the title product were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#N)[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.[OH:30]S(O)(=O)=O.[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:30])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCOc2cccc(C#N)c2)CC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CCCCOc2cccc(C=O)c2)CC1
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of 3-[4-(1-methyl-piperidin-4-yl)-butoxy]-benzonitrile (0.84 g, 3.09 mmol) in toluene (5 mL) at 0° C. was added 1.5 M DIBAL-H in toluene (4.63 mL, 4.63 mmol). After 3 h, methanol (9 mL) and 1.0 M H2SO4 (10 mL) were added dropwise. After stirring for 30 min, the solution was neutralized with 1.0 M sodium hydroxide (10 mL) followed by addition of satd. aq. sodium potassium tartrate (40 mL) and CH2Cl2 (100 mL). After stirring for 30 min the solution was extracted with CHCl3 (3×50 mL), washed with brine and dried over Na2SO4. Purification by Method 1 afforded 0.56 g (66%) of the title compound. 1H NMR (400 MHz, CDCl3): 9.97 (s, 1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.19-7.15 (m, 1H), 4.02 (t, J=6.6, 2H), 2.86-2.80 (m, 2H), 2.25 (s, 3H), 1.92-1.83 (m, 2H), 1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44 (m, 2H), 1.34-1.18 (m, 5H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)CCC.Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:6]3[CH:7]=[CH:8][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:13])=[O:14])=[CH:10][CH:11]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOC)cc3)cc3ccccc23)CC1
Yield: 66 %

Procedure:
(4-Tributylstannylphenyl)(3-methoxypropyl)sulfone (1.70 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.20 g) in xylene in nitrogen atmosphere for 1 day. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.87 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5](O)=[O:6].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:5](=[O:6])[CH:4]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[CH2:3][C:2]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:1])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCCC2
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].I[CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:14])[C:7]([CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: ICCc1cccs1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1cccs1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Sodium hydride (55%, 18.8 g, 0.43 mol) was suspended in dimethylformamide (200 ml), and methylmalonic acid diethylester (50.0 g, 0.29 mol) was slowly added thereto for 30 minutes in an ice bath, and then the reaction solution was stirred for 30 minutes. To the reaction solution was added 2-(2-iodoethyl)thiophene (75.2 g, 0.32 mol) dissolved in dimethylformamide (200 ml) under-a nitrogen atmosphere for 15 minutes, and then the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into ice-cold 10% hydrochloric acid (500 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=10:1-5:1) to afford the title compound (53.1 g, 65% yield) as a colorless oil.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1>>[CH:1]([C:6]1([OH:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)[Mg]Cl
Product: CC(C)C1(O)CCCc2ccccc21
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with 3,4-dihydro-1(2H)-naphthalenone (146 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.00 mL, 1.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as colorless oil (180 mg, 95%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.O>C(O)(=O)C>[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:1])=[CH:14][CH:15]=1
Reactant: OO
Reactant: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(S(C)=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrogen peroxide (1 equivalent, 30%) is added to a solution of 4-methyl-5-[4-(methylthio)benzoyl]-2(3H)-thiazolone (2.7 g) in glacial acetic acid (80 ml). The mixture is stirred for 3 hours at 50° C. The precipitate obtained on addition of water is recrystallized from ethanol to give the title compound.