Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](C(=O)OC)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reaction time: 2 h

Procedure:
Hydrazine hydrate (0.152 mL) was added to a stirred solution of methyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexanecarboxylate (913 mg) in EtOH (25 mL). The mixture was stirred for 2 hours. The precipitate was filtered off, washed with EtOH, and dried under vacuum to give the title compound (Intermediate 44, 277 mg) as a solid; 1HNMR δ 10.43 (1H, s), 7.67 (2H, d), 7.17 (2H, d), 4.52 (2H, s), 3.59 (3H, s), 2.53-2.33 (2H+DMSO, m), 1.97 (2H, m), 1.81 (2H, m), 1.46 (4H, m); MS m/e MH+ 320.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C)Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under inert gas atmosphere 303 mg (1.00 mmol) N-[2-(4-iodo-phenyl)-1-methyl-ethyl]-acetamide (III.2) are added to a mixture of 309 mg (1.00 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 49 mg (0.060 mmol) PdCl2(dppf)xCH2Cl2 and 415 mg (3.00 mol) K2CO3 in 5 mL DMF. The mixture is stirred for 48 h at rt. After that time, the solvent is evaporated, the residue taken up in ethyl acetate and washed with water. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; ethyl acetate) to yield the desired product.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=2[CH:5]=1)(=O)[CH3:2].[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C.C(O)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([C:1]3[NH:20][C:14]4[C:19]([CH:2]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:5][C:6]=2[CH:12]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1cc2cc(Br)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1ccc2oc(-c3cc4ccccc4[nH]3)cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 2-acetyl-5-bromobenzo[b]furan (commercially available, 5.0 g, 1 eq.) is initially charged in absolute ethanol. Phenylhydrazine (97%; 2.33 g, 1 eq.) is introduced. 20 drops of glacial acetic acid are added to this mixture and the reaction is stirred at room temperature for 24 h. Then phenylhydrazine (97%; 0.36 g, 0.15 eq.) is added and the mixture is stirred at room temperature for a further 5 h. The solids are filtered off and washed with distilled water. Dried under reduced pressure at 65° C. This gives 6.65 g of intermediate. This is introduced gradually into polyphosphoric acid (60 g), and the mixture is heated to 120° C. and stirred for a further 1 h. 0.5 l of distilled water is cautiously added dropwise to the reaction and the mixture is stirred for a further 2 h. The suspension obtained is neutralized with 50% sodium hydroxide solution. The suspension is filtered with suction and the solids are washed with distilled water. The solids obtained are dried under reduced pressure. This gives 6.07 g of slightly contaminated product (crude yield 93%). This is used in the next stage without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)cc1N
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol) and 2-methoxy-5-methylaniline (46 mg, 0.34 mmol) similar to Example 180. After completion of the reaction the solvent was removed under reduced pressure. The product was purified (5 mg) by preparative TLC plate using 1:1 hexane/ethyl acetate as mobile phase. 1H NMR (DMSO-d6): 9.68 (s, 1H), 8.75(d, J=3.6, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.00 (t, J=7.2 Hz, 1H), 7.55 (dd, J=4.0, 7.2 Hz, 1H), 7.04 (m, 2H), 3.82 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[CH3:1][N:2]([CH2:3][CH2:4][CH3:5])[S:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:34]2[CH:33]=[C:32]([C:18]3[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH:37]=[CH:36][N:35]=2)[CH:39]=1)(=[O:45])=[O:46]
Reactant: CCCNC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylpropylamine (0.23 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.47 g, 86%). MS (ISP) 580.6 [(M+H)+]; mp 144° C.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)(Cl)Cl>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([N+:13]([O-:15])=[O:14])[CH2:5][O:6][CH2:7][CH:8]1[O:21][CH2:9]1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C(COCC1CO1)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 60.5 %

Procedure:
A solution of allyl trinitroethyl ether (111 g, 502 mmol) in chloroform (100 ml) was added to the mechanically stirred mixture of m-chloroperoxybenzoic acid (102 g, 590 mmol) and chloroform (450 ml). The mixture was refluxed at 70° C. for 6 h under nitrogen. The mixture was cooled with an ice bath for 30 min and filtered. The filtrate was concentrated and additional precipitate was filtered out. The filtrate was diluted with methylene chloride, washed with 10% sodium thiosulfate, saturated sodium bicarbonate, water and dried. Solvent was removed under vacuum. The golden yellow liquid residue (109 g) was chromatographed in portions using silica gel and methylene chloride to give 72 g (60% yield) of glycidyl trinitroethyl ether: 1HNMR (CDCl3) 2.64 (d of d, 1H), 2.87 (t, 1H), 3.22 (m, 1H), 3.53 (d of d, 1H), 4.15 (d of d, 1H), 4.85 (AB quartet, 2H) ppm; IR (neat): 3067 (w), 3006 (m), 2932 (m), 1591 (br, vs), 1454 (m), 1340 (m), 1305 (s), 1254 (m), 1161 (m), 1138 (s), 1082 (m), 1032 (w), 988 (w), 945 (w), 900 (m), 880 (m), 855 (m), 804 (s), 782 (m) cm−1.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)C1C=CC=CC=1>CO.[Pd]>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:14][C:13](=[O:15])[CH2:12]1
Reactant: O=C1C[C@H](C2OCCO2)[C@@H](COCc2ccccc2)O1
Agent: [Pd]
Solvent: CO
Product: O=C1C[C@H](C2OCCO2)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
To a solution of dihydrofuranone (14) (0.5 g, 1.79 mmol) in MeOH (30 mL) was added Pd/C (25 mg). The mixture was stirred at room temperature under an H2 balloon for 24 hours, and then filtered over Celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent) yielded the compound (15) (301 mg, 89%) as a white solid, Rf=0.28 (50% EtOAc in hexanes), [α]25D 22° (c 1.32, CHCl3); 1H-NMR (500 MHz, CDCl3) δ: 2.54 (dd, 1H, J=6.0, 11.4 Hz), 2.68-2.81 (m, 2H), 3.66 (dd, 1H, J=3.9-8.5 Hz), 3.88-3.95 (m, 3H), 3.97-4.02 (m, 2H), 4.53 (m, 1H), 4.91 (d, 1H, J=3.9 Hz); 13C-NMR (125.8 MHz, CDCl3) δ: 30.68, 40.12, 64.36, 65.77, 81.07, 103.94, 176.83.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.[CH3:17][NH2:18]>CC(O)C>[CH3:15][N:5]1[C:4](=[O:16])[CH:3]=[C:2]([NH:18][CH3:17])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]1=[O:14]
Reactant: Cn1c(=O)cc(Cl)n(-c2ccccc2)c1=O
Reactant: CN
Solvent: CC(C)O
Product: CNc1cc(=O)n(C)c(=O)n1-c1ccccc1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
The obtained 6-chloro-3-methyl-1-phenyluracil (4.26 g, 18 mM) was added to 100 ml of 2-propanol. A 40% aqueous solution of methylamine (17 g, 0.22M) was added to the resulting solution and the mixture was heated at 90° C. for 5 hours while stirring. After being left to cool, a precipitated crystal was obtained by filtration and washed successively with ethanol and water to yield 3-methyl-6-methylamino-1-phenyluracil (yield: 3.71 g, or 89% based on 6-chloro-3-methyl-1-phenyluracil).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2ncc(C(=O)O)c(Br)c2c1
Reaction time: 24 h

Procedure:
To a solution of the ethyl 4-bromo-6-(methyloxy)-3-quinolinecarboxylate (12 g, 38.7 mmol) in THF (120 mL) was added 2N NaOH (45 mL, 90 mmol) dropwise over 15 min. The reaction solution was stirred for 24 h and then neutralized with 2N HCl (pH 6). The THF was removed in vacuo and the resulting aqueous solution was acidified to pH 2. The product was collected by filtration and washed with water and fully dried under vacuum (48 h). Isolated 10.8 g (100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=12.[H-].[Na+].I[CH3:21]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:21])[C:6]=12
Reactant: CI
Reactant: Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)nn2c1N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-2-(pyridine-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-one (50 mg, 0.22 mmol) in DMF (5 mL) was added NaH (13 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and then iodomethane (47 mg, 0.33 mmol) was added and stirred at room temperature for 30 minutes. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were dried, filtered, concentrated in vacuo and re-crystallized from MeOH to give 3,4-dimethyl-2-(pyridine-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4 H)-one: MS (m/z): 243.1 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.55 (d, 1 H, J=4.0 Hz), 8.03 (d, 1 H, J=8.0 Hz), 7.54 (dd, 1 H, J=4.8 Hz, J=8.0 Hz), 4.35 (t, 2H, J=6.8 Hz), 3.50 (s, 3 H), 2.95 (t, 2 H, J=6.8 Hz), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([OH:41])[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([O:41][C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(OC(=O)Nc3ccc(Cl)cc3)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
4-Chlorophenyl isocyanate (32 mg, 0.208 mmol) and DMAP (5 mg) were successively added to a solution of Example 62 (100 mg, 0.21 mmol) in toluene (20 ml) and stirred at 90° C. for 30 min. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The organic phase was washed with dilute citric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from methanol resulted in 80 mg of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>Cl.O>[CH:18]1[C:19]2[C:14](=[C:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
5-(4-Nitrophenylsulfonyl)isoquinoline 160 mg (0.6 mmol) was dissolved in concentrated hydrochloric acid 170 ml, stannous chloride dihydrate 650 mg (2.9 mmol) was added, and the mixture was stirred overnight at room temperature. 4 N sodium hydroxide in water was added to the reaction solution, and the resulting alkaline solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from methanol to give 4-(5-isoquinolylsulfonyl)aniline 110 mg (76.5%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(C(=O)OCC)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCNc1nc(CO)cs1

Procedure:
The reaction described in Preparation 15 was repeated, but using 10 g of ethyl 2-allylaminothiazole-4-carboxylate, 2.7 g of lithium aluminum hydride and 150 ml of tetrahydrofuran. giving the title compound as pale brown needles.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][C:20]=1[O:21][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)[CH:14]=[O:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1ccc2ccccc2c1
Yield: 76.3 %

Procedure:
2-(Bromomethyl)naphthalene (1.3 g, 5.9 mmol) was added to a suspension of vanillin (0.60 g, 3.9 mmol) and potassium carbonate (1.6 g, 12 mmol) in acetone (10 mL) and treated according to Procedure 3. The crude product was recrystallised from EtOAc/petrol providing 3-methoxy-4-(naphth-2-ylmethoxy)benzaldehyde (0.87 g, 75%) as a colourless crystalline solid; mp 107-108° C.; δH (400 MHz, CDCl3) 3.97 (s, 3H, OCH3), 5.41 (s, 2H, OCH2), 7.38 (m, 1H, Naphth-H), 7.44 (d, J2,6=1.6 Hz, 1H, H2), 7.48-7.50 (m, 3H, H6, Naphth-H), 7.55 (m, 1H, Naphth-H), 7.83-7.89 (m, 4H, Naphth-H), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.3, 71.3 109.7, 112.8, 125.1 126.4, 126.5, 126.6, 126.8, 128.0, 128.2, 128.9, 130.6, 133.4, 133.5, 133.7, 150.4, 153.8, 191.1; vmax 991, 1131, 1263, 1505, 1580, 1672, 2884 cm−1.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25]([O:27]C)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:29][CH3:30])[C:25]([OH:27])=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)O)C1=O
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (200 mg, 0.42 mmol; Example 91, Step A) in THF (5 mL) was added sodium hydroxide (506 mg, 12.65 mmol) in water (5 mL) and the reaction was heated at reflux for about 12 h. After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and 1.0 M HCl (20 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated in vacuo to give the title compound as a white solid. Mass Spectrum (ESI) m/z=460.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[OH:11][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[C:4]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN1CCNCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Temperature: 100 °C

Procedure:
A mixture of 1-methylpiperazin-2-one (183 g, 1.6 mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to −20° C., and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: CS(O[CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].N(C(CCCCCCCCCC)CCCCCNC1C=CC(C(O)=O)=CC=1)=[N+]=[N-]>CN(C)C=O>[N:34]([CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[N+:35]=[N-:36]
Reactant: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)O)cc1)N=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)N=[N+]=[N-]

Procedure:
A solution of 6.4 g. of ethyl 4-(6-methanesulfonyloxyhexadecylamino)benzoate and 1.9 g. of sodium azide in 65 ml. of dimethylformamide is stirred at ambient temperature for 16 hours, poured into 200 ml. of water, and extracted with chloroform. The organic extract is washed with saturated sodium chloride solution, dried over sodium sulfate, the evaporated. Crystallization of the residue from hexane yields the product. The ester is hydrolyzed to 4-(6-azidohexadecylamino)benzoic acid using the procedure of Example 10.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](\[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([CH3:11])(=[O:10])=[O:9])/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: CS(=O)(=O)c1ccccc1I
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3S(C)(=O)=O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-2-methanesulfonyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.89 (s, 1.5H), 2.50 (s, 1.5H), 3.90 (s, 3H), 4.98 (dd, 2H), 5.98 (dd, 1H), 6.65-6.68 (m, 2H), 7.07 (m, 1H), 7.35-7.58 (m, 8H), 7.61 (t, 1H), 7.78 (t, 1H), 7.99 (d, 1H), 8.02 (d, 1H), 8.20 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCNCC3)c3ccccc3)ccc12
Reactant: CC(C)=O
Product: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCN(C(C)C)CC3)c3ccccc3)ccc12

Procedure:
Using alkylation method A, 3-methyl-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (400 mg, 1.0 mmol) and acetone (0.75 mL, 10 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 197 mg (44%) of the title compound.