Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH:16]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: OCCc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(CCO)cn1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
To a solution of 1.0 gm (9.0 mMol) 2-(4-pyrazolyl)-1-ethanol in 36 mL dimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonate followed by the dropwise addition of a solution of 0.89 mL (9.0 mMol) 2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was then cooled to ambient and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was then washed with water followed by saturated aqueous sodium chloride and was then dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 0.36 gm (26.0%) of the title compound as a brown oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:13](=[N:14][N:15]([CH3:19])[C:16]=3[OH:18])[C:12](=[O:20])[N:11]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:6][CH:5]=1.I[CH2:31][CH3:32]>CN(C=O)C.CCOC(C)=O.O.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:13](=[N:14][N:15]([CH3:19])[C:16]=3[O:18][CH2:31][CH3:32])[C:12](=[O:20])[N:11]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(N2C(=O)c3nn(C)c(O)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c2c(nn1C)C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
NaH (19.19 mg, 0.48 mmol) was added to a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-hydroxy-2-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6-(2H)-one (Example 73) (142 mg, 0.369 mmol) in DMF (1 mL) at 0° C. and the reaction was stirred at 0° C. for 20 min. Iodoethane (0.036 mL, 0.443 mmol) was added and the resulting mixture was stirred at RT for 20 min. The reaction was diluted with EtOAc and water and both phases separated. The aq. layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (1% ammonia/7.5% MeOH/CH2Cl2) to afford, after trituration in Et2O, the title product (77 mg, 0.186 mmol, 50% yield) as white solid. tR: 0.91 min (LC-MS 2); ESI-MS: 413 [M+H]+ (LC-MS 2); Rf=0.39 (1% ammonia/7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=6.8 Hz, 3H) 1.91 (s, 3H) 3.35 (s, 3H) 3.60-3.77 (m, 4H) 3.89-4.03 (m, 1H) 6.20 (s, 1H) 7.25 (d, J=8.6 Hz, 2H) 7.30-7.44 (m, 3H) 7.66 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.NCC(O)=O.[O:15]1[CH:19]=[CH:18][CH2:17][CH2:16]1>CN(C)C=O>[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: NCC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 145 °C

Procedure:
In 20 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.75 g of glycin. 2.8 Grams of 2,3-dihydrofuran in several portions were added in 8 hours to the solution while heating it at 145° C. The mixture was then reacted for 5 hours at the same temperature. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 16. 0.9 g of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained and 1.0 g of 5-fluorouracil containing 0.75 g of glycin was recovered. The yield of the end product was 56% based on the consumed 5-fluorouracil.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:1]([NH:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:38](=[O:39])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[CH:32]([O:31][C:28](=[O:30])[CH3:29])[C:41]([CH3:47])([CH3:48])[CH2:42][O:43][C:44](=[O:46])[CH3:45])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(N)cc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(NC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O)cc1
Yield: 68.5 %

Procedure:
4-Oleoylaminoaniline (744 mg) and 606 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 900 mg of the title compound (yield: 69%).
Reaction SMILES: C([O:8][C:9]1[C:41]([O:42][CH3:43])=[CH:40][C:12]2[C:13](=[O:39])[N:14]3[CH2:38][CH2:37][CH2:36][C@H:15]3[C@H:16]([O:25][CH:26]3[C:31]([OH:32])=[C:30]([OH:33])[C:29]([OH:34])=[C:28]([OH:35])[O:27]3)[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CCCCCC>[OH:8][C:9]1[C:41]([O:42][CH3:43])=[CH:40][C:12]2[C:13](=[O:39])[N:14]3[CH2:38][CH2:37][CH2:36][C@H:15]3[C@H:16]([O:25][CH:26]3[C:31]([OH:32])=[C:30]([OH:33])[C:29]([OH:34])=[C:28]([OH:35])[O:27]3)[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N(C(=O)OC(C)(C)C)[C@@H](OC1OC(O)=C(O)C(O)=C1O)[C@@H]1CCCN1C2=O
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2c(cc1O)N(C(=O)OC(C)(C)C)[C@@H](OC1OC(O)=C(O)C(O)=C1O)[C@@H]1CCCN1C2=O
Yield: 89.3 %

Procedure:
A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 13 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3 h at 35 Psi. When the reaction was complete as indicated by TLC (SiO2, 50% EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 14 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [α]20D=+84° (c=0.48, CHCl31H NMR (CDCl3, 400 MHz): δ 1.35 (s, 18H, Boc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, 11a-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13C NMR (CDCl3, 400 MHz): δ 19.9, 20.7, 23.1, 23.2, 25.1, 25.3, 28.0, 28.1, 28.9, 29.1, 30.8, 31.2, 46.3, 56.13, 56.19, 60.0, 60.2, 63.4, 64.5, 81.0, 81.1, 87.9, 91.1, 95.8, 100.7, 109.6, 110.0, 116.4, 117.0, 125.5, 125.9, 130.2, 130.5, 145.7, 145.8, 147.4, 147.5, 154.9, 155.3, 167.4, 167.6; IR (neat): 3266, 2947, 1703, 1631, 1612, 1514, 1468, 1411, 1368, 1331, 1275, 1201, 1163, 1116, 1023 cm−1; MS (FAB) m/z (relative intensity) 471 ([M+Na]+., 15), 449 (M+., 99), 246 (100), 347 (25).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[Cl:22].BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[Cl:22]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(Cl)c2)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-3-chloro-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C17H17BrClNO (m/e) 367, obsd 368 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Br:21].[N+]([O-])(O)=[O:23].O>CC(O)=O>[Br:1][C:2]1[C:19](=[O:20])[C:18](=[O:23])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Br:21]
Reactant: O=C(c1ccc(F)cc1)c1coc2c(Br)c(Br)c(O)cc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(=O)c2c(C(=O)c3ccc(F)cc3)coc2C(Br)=C1Br
Temperature: 60 °C
Yield: 21.8 %

Procedure:
To a solution of (6,7-dibromo-5-hydroxybenzofuran-3-yl)(4-fluorophenyl)methanone (62 mg, 0.150 mmol) in AcOH (1 mL) was added nitric acid—69% (46.2 μl, 0.749 mmol) at room temperature. The mixture was heated to 60° C. for 3 hours, cooled to room temperature, poured onto iced water and the suspension filtered. A solid was isolated which was dried under vacuum to afford the product (14 mg, 17%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([O:32]C)=[O:31])[C:20]3=[O:34])=[CH:12][C:11]=1[F:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:34])=[CH:12][C:11]=1[F:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccc(CNC(=O)OC(C)(C)C)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Yield: 85.7 %

Procedure:
A solution of methyl 8-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (24 mg, 0.050 mmol) and an aqueous 1N sodium hydroxide solution (0.500 mL, 0.500 mmol) in MeOH (2 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled. The MeOH was removed under reduced pressure, the residue was taken-up in water (5 mL) and then neutralized with a 1N hydrochloric acid solution (−0.5 mL). A precipitation was formed and the mixture was extracted with DCM (3×4 mL). The organic layer was concentrated to give the acid (20 mg, 86%).
Reaction SMILES: [K+].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Br:21][C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[C:24]([Cl:31])[CH:23]=1>C(#N)C>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:4](=[O:6])[CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[C:24]([Cl:31])[CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
13bs) 6.8 g of monoethyl malonate potassium salt in 70 ml of acetonitrile were cooled to 10° under argon and treated with 5.3 ml of triethylamine and 4.8 g of magnesium chloride. The resulting thick suspension was stirred at room temperature for 2 hrs. Then, it was again cooled to 10° and 5 g of 4-bromo-2-chloro-benzoyl chloride were added dropwise thereto over 30 min. The mixture was stirred at room temperature for 15 hrs. and then concentrated. Extraction: twice with 100 ml of toluene, once with 100 ml of cold 1N HCl and twice with 100 ml of water. After drying and evaporation there were obtained 5.2 g (85%) of ethyl 3-(4-bromo-2-chlorophenyl)-3-oxo-propionate as a brown oil which crystallized in a refrigerator. M.p. 34° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.2 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (70.8 mg, 0.339 mmol) was dissolved in THF (5 mL) and lithium borohydride (25.9 mg, 1.187 mmol) was added. The reaction was allowed to reflux under argon for three hours and was then allowed to stir overnight at room temperature. The reaction was quenched with 1M hydrochloric acid and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the title compound as a white solid (75.8 mg, 106%). 1H NMR (CDCl3) δ (ppm): 8.190 (s, 1H), 8.070 (m, 1H), 7.507 (m, 2H), 5.082 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[N+]=[N-])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[FH:12]>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[C:7]=1[F:12])[NH2:9]
Reactant: Cc1cc(C)cc(N=[N+]=[N-])c1
Reactant: F
Solvent: CCCCCC
Product: Cc1cc(N)cc(C)c1F
Temperature: 0 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
The 95 ml. hexane solution of 3,5-dimethylphenylazide prepared in Step A above was charged to a rocker bomb and 20 ml. of hydrogen fluoride was added. The reaction mixture was then aged for 10 hours at room temperature with agitation, after which it was cooled, vented, and poured from the bomb, and the bomb rinsed with 40 ml. of water and 40 ml. of dichloromethane. The combined hexane, dichloromethane and hydrogen fluoride were blown down under nitrogen. The resulting residue was combined with the aqueous rinse, cooled to 0° C., and rendered alkaline with KOH pellets. The residue was then extracted three times with 75 ml. of dichloromethane per extraction, and the combined extracts dried over MgSO4 and then concentrated under reduced pressure to yield 7.34g. (66.2%) of a brown-red oil. This oil was then vacuum distilled at 40 mm. Hg to give 6.70g. of a colorless oil, a 60% yield. The final product had a b.p. of 127°-130° C. at 40 mm. Hg.
Reaction SMILES: [OH:1][CH:2]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH2:58][CH2:59][OH:60])[C:52]([CH3:62])([CH3:61])[CH2:51]2)[NH:47][C:46]1=[O:63])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:43])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([CH2:37][CH2:38][OH:39])[C:31]([CH3:41])([CH3:40])[CH2:30]4)[NH:26][C:25]3=[O:42])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.C(O[C:68](=[O:70])[CH3:69])(=O)C>>[C:17]([O:1][CH:2]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:51][C:52]([CH3:62])([CH3:61])[N:53]([CH2:58][CH2:59][O:60][C:2](=[O:1])[CH3:3])[C:54]([CH3:57])([CH3:56])[CH2:55]2)[N:47]([C:68](=[O:70])[CH3:69])[C:46]1=[O:63])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([O:43][C:5](=[O:4])[CH3:6])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:30][C:31]([CH3:40])([CH3:41])[N:32]([CH2:37][CH2:38][O:39][C:38](=[O:39])[CH3:37])[C:33]([CH3:35])([CH3:36])[CH2:34]4)[N:26]([C:28](=[O:29])[CH3:27])[C:25]3=[O:42])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1)(=[O:20])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(c1ccc(OCC(O)CN2C(=O)NC3(CC(C)(C)N(CCO)C(C)(C)C3)C2=O)cc1)c1ccc(OCC(O)CN2C(=O)NC3(CC(C)(C)N(CCO)C(C)(C)C3)C2=O)cc1
Product: CC(=O)OCCN1C(C)(C)CC2(CC1(C)C)C(=O)N(CC(COc1ccc(C(C)(C)c3ccc(OCC(CN4C(=O)N(C(C)=O)C5(CC(C)(C)N(CCOC(C)=O)C(C)(C)C5)C4=O)OC(C)=O)cc3)cc1)OC(C)=O)C(=O)N2C(C)=O
Temperature: 0 °C

Procedure:
A mixture of 1 g of 2,2-bis{4-[2-hydroxy-3-(8-β-hydroxyethyl-7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane (obtained as described in Example 18) and 20 g of acetic anhydride was refluxed for 60 hours. After completion of the reaction, the reaction mixture was poured into ammoniacal ice-water, extracted with benzene and then purified by column chromatography through silica gel eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give the desired Compound No. 188 in the form of white crystals. The compound had an Rf value of 0.86 on thin-layer chromatography on silica gel using a 1:1:1 by volume mixture of n-hexane, benzene and ethyl acetate as developing solvent.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1>O1CCCC1.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc3ccccc3s2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2nc3ccccc3s2)cc1

Procedure:
150 parts by weight of β-(benzothiazol-2-yl)-4-nitrostyrene were dissolved in 1,500 parts by volume of tetrahydrofuran, and 15 parts by weight of Pd/C (10%) were added. After the mixture had been flushed with nitrogen, hydrogen was passed in. After some hours, the uptake of hydrogen (44 1) had ended, and the mixture was flushed with nitrogen again, the catalyst was filtered off and the filtrate was concentrated. 135.6 g of 4-(β-benzothiazol-2-yl-ethyl)-aniline of melting point 79°-81° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with p-toluidine to yield 2-[(4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.COC(=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].Cl>C(Cl)(Cl)Cl.O>[CH2:14]([C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccnc1
Reactant: COC(=O)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Cc1ccccc1)c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 27.4 g (0.2 mol) of nicotinic acid methyl ester and 30 g (0.2 mol) of phenylacetic acid methyl ester is treated in small amounts under nitrogen with 16.2 g (0.3 mol) of sodium methylate at 20°-25°C. The reaction mixture is stirred for 20 hours at 60°-70°C, in the process of which the alcohol which is formed is blown off. Then 60 ml of concentrated hydrochloric acid is added dropwise to the solid substance and the mixture is boiled for 3 hours under reflux. The still hot yellow solution is treated with 30 ml of water and cooled to 50°C. Then 60 ml of chloroform are added and the reaction mixture is cooled to 5°C. The white crystals which form are collected by suction filtration and washed with chloroform; they melt at 225°C (from ethanol).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].C([Mg]Br)C.Br[CH2:17][C:18]#[C:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:17][C:18]#[C:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC#CCC#CCBr
Reactant: C#CCCCCCCC(=O)O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCC#CCC#CCC#CCCCCCCC(=O)O
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of non-8-ynoic acid (nD25 1.4529, m.p. 20°-2°; 30.8 g, 0.2 mol) in tetrahydrofuran (100 ml) was added a 1.45 M solution (275 ml) of ethylmagnesium bromide in tetrahydrofuran during 30 minutes at 0°. The resulting mixture was stirred for 21/2 hours, after which cuprous cyanide (720 mg, 4 mmol) was added and stirring was continued for 10 minutes. A solution of 1-bromododeca-2,5-diyne (Struyk et al., loc.cit., b.p. 78°-80°/0.001 mm Hg, nD25 1.5055; 36.2 g, 0.15 mol) in tetrahydrofuran (75 ml) was then added during 10 minutes, and the stirred mixture heated to boiling and boiled under reflux for 15 hours: at the end of the first 4 hours another portion of cuprous cyanide (360 mg) was added. After refluxing was completed the bulk of the solvent present was distilled off under reduced pressure and to the cooled residue were added ether (100 ml) and aqueous 2N sulphuric acid. The mixture was thoroughly shaken, the ether layer which formed on standing was separated off and the aqueous layer extracted with ether; the combined ether layers were washed with saturated aqueous ammonium chloride solution, then with water, dried with anhydrous sodium sulphate and evaporated. The residue was dissolved in a small quantity of light petroleum and the solution chromatographed on a column (30 cm length and 2.2 cm diameter) of silica gel using as eluant mixtures of light petroleum and ether commencing with a proportion by volume of 95:5 and proceeding with increasing proportions of ether, with a final proportion of 40:60. The eluted fractions found to contain acid were combined and evaporated: the residue was crystallised from a mixture of light petroleum and ether (85:15 by volume) at -5° to give heneicosa-8,11,14-triynoic acid (22.7 g, 48%), m.p. 57°-8°; infrared absorption peaks at 1690 (--COOH) and 1309 cm-1 (--CH2C≡C--). The acid was converted by reaction with an ether solution of diazomethane to its methyl ester which was submitted to GLC and shown to be of 99.5% purity; mass spectrum parent peak m/e=328.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([OH:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(O)c1cccc2cnccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a 10° C. solution of 1-(isoquinolin-5-yl)ethanol (530 mg, 3.0 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.9 g, 4.0 mmol) under a N2 atmosphere. The reaction mixture was stirred for 16 h at room temperature and then quenched with saturated NaHCO3 solution (5 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford 1-(isoquinolin-5-yl)ethanone (500 mg, 95.4%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:15]([O-])=O)=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[NH2:15][C:12]1[N:11]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]2=[N:14][CH:13]=1
Reactant: CCOC(=O)c1cccc2ncc([N+](=O)[O-])n12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc2ncc(N)n12
Temperature: 25 °C
Reaction time: 110 h
Yield: 43.5 %

Procedure:
To a solution of 2.35 g of 5-ethoxycarbonyl-3-nitroimidazo[1,2-a]pyridine in 100 ml of ethanol was added 10% Pd-C (wet, 470 mg). The mixture was stirred for 110 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with ethanol. The filtrate and the washing were combined, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to afford 891 mg of the desired compound (43.4%, a dark reddish oil).