Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.Cl[CH2:39][O:40][C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44].[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([O:35][CH2:39][O:40][C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COC(=O)N[C@H](C(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added (S)-2-methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (112 mg, 503 μmol), NaI (101 mg, 670 μmol), 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1) to yield the title compound as a white solid (8.4 mg). LC-MS: 712.9 [M+H]+. 1H NMR: (MeOD, 400 MHz) δ 0.85 (dd, J=14.1, 6.8 Hz, 6H), 2.01-2.17 (m, 1H), 3.42-3.51 (m, 2H), 3.69 (s, 3H), 4.00 (d, J=5.9 Hz, 1H), 4.23 (br, 2H), 4.42 (t, J=4.7 Hz, 1H), 5.83 (dd, J=31.5, 5.6 Hz, 2H), 7.19 (t, J=9.4 Hz, 1H), 7.32-7.39 (m, 3H), 7.47-7.51 (m, 4H), 7.56-7.58 (m, 2H), 7.91 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Benzyloxy-3-methoxybenzaldehyde (4.85 g) was added to nitric acid (d=1.42, 20 mL) in a dropwise manner over 1 hour at room temperature, and this mixture was stirred for 1 hour. This reaction mixture was poured into ice water and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (4.99 g). To this product was added acetic acid (50 mL), followed by adding nitromethane (3.19 g) and ammonium acetate (5.36 g), and this mixture was stirred for 5 hours at 100° C. This reaction mixture was concentrated under reduced pressure. To this residue was added water and the precipitated solid was collected by filtration, and this solid was washed with methanol, dried to give 1-benzyloxy-2-methoxy-5-nitro-4-(2-nitrovinyl)benzene (4.03 g). To this compound were added benzene (96 mL), acetic acid (72 mL) and cyclohexane (24 mL), followed by adding silica gel (18 g) and iron powder (10.2 g), and this mixture was stirred at 100° C. for 1 hour. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (1.06 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11](O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].O1CCOCC1.[ClH:29]>CCOCC>[Cl:29][CH:11]1[C:10]2[CH:21]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:7]=[CH:8][C:9]=2[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: Cl
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reaction time: 5 h

Procedure:
A solution of 1.0 g. (0.00317 mole) of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol in a mixture of 2 ml. of dry dioxane and 2 ml. of absolute ether is cooled in ice and saturated with dry hydrogen chloride. The mixture is allowed to stand at room temperature for 5 hours and then is refrigerated overnight. The white crystalline product is collected, washed with petroleum ether, and dried in a vacuum desiccator over calcium chloride. The yield of 5-chloro-3-dimethylsulfamoyl-5H-dibenzo-[a,d]cycloheptene is 600 mg,. m.p. 139.5°-143.5°C. Dilution of the mother liquor with petroleum ether gives a second crop which is recrystallized from a mixture of ether and petroleum ether affording 250 m.g., m.p. 138.5°-142.5°C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26]CC(O)=O)[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]>ClCCl.CN(C=O)C>[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:1][C:2]([Cl:4])=[O:3])[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2cnc3cccnc3c2n1CCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A solution of oxalyl chloride (2.04 mL, 23.4 mmol) in dichloromethane (15 mL) was added dropwise to a suspension of 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoic acid (2.56 g, 7.8 mmol) in dichloromethane (38 mL) containing one drop of DMF. The reaction mixture was stirred at ambient temperature for 1.75 hours, and then additional oxalyl chloride (0.35 mL, 4.1 mmol) was added. The reaction was stirred for an additional 45 minutes and then concentrated under reduced pressure to provide 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoyl chloride.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH2:20][CH:19]4[CH:21](C(O)=O)[CH:16]([CH2:17][CH2:18]4)[CH:15]=3)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C([O-])(O)=[O:30].[Na+]>C1COCC1>[O:30]=[C:21]1[CH:16]2[CH2:17][CH2:18][CH:19]1[CH2:20][CH:14]([C:7]1[NH:6][C:5]3[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=3[N:8]=1)[CH2:15]2
Reactant: CCCn1c(=O)c2[nH]c(C3=CC4CCC(C3)C4C(=O)O)nc2n(CCC)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4=O)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
The product (390 mg) from Example 35, was taken in THF (10 ml) 6N HCl (3 ml) and heated to reflux overnight. The next day, after cooling to room temperature, poured over ice, neutralized with NaHCO3, extracted with ethyl acetate, washed with brine and dried over MgSO4. Filtered, concentrated, and purified on silica. Yield (321 mg). Mass (ES+ 359).
Reaction SMILES: C([O:8][C:9]1[CH2:13][N:12]([CH2:14][C:15]([NH2:17])=[O:16])[C:11](=[O:18])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].[Pt]=O>[OH:8][CH:9]1[CH2:13][N:12]([CH2:14][C:15]([NH2:17])=[O:16])[C:11](=[O:18])[CH2:10]1
Reactant: NC(=O)CN1CC(OCc2ccccc2)=CC1=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
3.00 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide was dissolved in 30 ml of concentrated acetic acid and mixed with 240 mg of palladium 5 percent on activated carbon and 24 mg of platinum oxide. Hydrogenolysis and hydrogenation at 15 bars of hydrogen pressure and room temperature were performed for 65 hours. Then filtering off from the catalyst and evaporation of the solvent were performed. The residue was picked up in H2O and allowed to run over 5.0 g of weakly basic ion exchanger. The water was distilled off and the residue mixed with 10 ml of acetone. 1.53 g of nearly white 4-hydroxypyrrolidin-2-on-1-yl acetamide with a melting point of 163.5° to 165.7° C. was obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([C:2]1[N:1]([CH2:6][C:7](=[O:8])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cn1cccc1)c1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a chilled (0° C.) solution of the 2-(1H-pyrrol-1-yl)-1-[5-(trifluoromethyl)pyridin-2-yl]ethanone (100 mg, approx. 90% pure, 0.35 mmol) in dry CH2Cl2 (5 mL) was added trichloroacetyl chloride (90 μL, 0.80 mmol) under nitrogen. The mixture was allowed to warm to room temperature. After completion (44 hours, monitored by LCMS) the mixture was cooled to 0° C. and quenched with a saturated aqueous solution of NaHCO3 (5 mL). The aqueous layer was then extracted with CH2Cl2 (2×2 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to yield a residue that was purified by flash chromatography (Biotage, 12 g cartridge, gradient hexanes 1 CV, 0-60% EtOAc in hexanes 10 CV) to give 2,2,2-trichloro-1-(1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrol-2-yl)ethanone as an orange oil (105 mg, yield: 75%). ESI-MI m/z [M+H]+ 398.9.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl[C:10]1[C:15]([C:16]2[N:24]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:18]([C:25]#[N:26])[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>ClCCCl>[Br:1][C:17]1[C:18]([C:25]#[N:26])=[C:19]2[N:24]([C:16]=1[C:15]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(-c2cccnc2Cl)n2c1CCCC2
Solvent: ClCCCl
Product: N#Cc1c(Br)c(-c2cccnc2)n2c1CCCC2
Yield: 68 %

Procedure:
2.42 g of N-bromosuccinimide are added with stirring to a solution of 3.5 g of 3-(2-chloro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile in 50 cm3 of 1,2-dichloroethane. The mixture is refluxed for 20 hours. After cooling, the reaction mixture is concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. The residue is taken up with 100 cm3 of ethyl acetate and washed 3 times with 70 cm3 of an aqueous solution of sodium bicarbonate at a concentration of 5%. The organic extracts are combined and dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at reduced pressure (2.7 kPa) at a temperature close to 50° C. A mixture of products is thus obtained, which is chromatographed on a column of 1.8 cm diameter containing 90 g of silica (0.04-0.0063). Elution is carried out with dichloromethane at a total pressure of 1.5 bar and with 20-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. 2.79 g of 2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of white crystals melting at 188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([C@@H:15]([CH3:26])[CH2:16][NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:25])[NH:23][CH:24]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].I[CH:28]([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([C@@H:15]([CH3:26])[CH2:16][NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:25])[N:23]([CH:28]([CH3:30])[CH3:29])[CH:24]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: CC(C)I
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C(C)C

Procedure:
The title compound was prepared using the method of Example 253 starting from (S)—N-{2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide and 2-iodopropane. 1H NMR (400 MHz, CDCl3): 1.42 (31-1, d), 1.43 (3H, d), 1.60 (3H, d), 2.37 (3H, s), 3.77 (1H, m), 3.88 (1H, m), 4.28 (1H, m), 4.63 (1H, m), 6.58 (1H, d), 7.50 (1H, d), 7.51 (1H, t), 7.59 (1H, s), 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[F:34])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:27]1[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=1[C:24]1[CH2:23][C:22](=[O:35])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cc(C#N)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(F)c(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K72) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (92 mg).
Reaction SMILES: [Se](=O)=O.[O:4]1[CH2:9][CH2:8][O:7]CC1.C([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=O)C>O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:8](=[O:7])[CH:9]=[O:4]
Reactant: C1COCCO1
Reactant: CC(=O)c1cccs1
Agent: O=[Se]=O
Solvent: O
Product: O=CC(=O)c1cccs1
Temperature: 55 °C

Procedure:
Al mixture of 27.5 g of selenium dioxide, 160 ml of dioxane and 5.5 ml of water was heated at 55° C. until solution was complete. A 31.54 g portion of 2-acetylthiophene was added and the mixture was refluxed for 4 hours, then cooled, filtered and evaporated under reduced pressure. The residue was distilled giving 24.5 g of 2-thiopheneglyoxylaldehyde.
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:6].[CH3:8][C:9]([CH3:14])=[CH:10][C:11](O)=[O:12]>C1(C)C=CC=CC=1>[CH3:8][C:9]1([CH3:14])[CH2:10][C:11](=[O:12])[NH:7][C@H:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[NH:6]1
Reactant: N[C@@H]1CCC[C@@H]1N
Reactant: CC(C)=CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N[C@H]2CCC[C@H]2N1
Temperature: 25 °C
Yield: 24 %

Procedure:
A toluene (200 mL) suspension of cis-cyclopentane-1,2-diamine (19.7 g, 197 mmol) and 3-methyl-2-butenoic acid (19.7 g, 197 mmol) was stirred under reflux for 24 hours under azeotropic conditions using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the deposited crystal was collected by filtration. The obtained crystal was washed with ether and then dried to obtain cis -4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one (8.60 g, 24%) in a light brown powder form.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1-Hydroxybenzotriazole (0.59 g) is added to a solution of (S)-2-[2-methoxyphenyl]propionic acid (0.75 g) of 84% optical purity prepared by the method of T. Matsumoto et al: Bull. Chem. Soc. Jpn., 58, 340 (1985), in dry dimethylformamide (15 cc) and the solution is then cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (0.91 g) is added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.44 g) and N,N-diisopropylethylamine (0.76 cc) in dimethylformamide (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, diluted with ethyl acetate (100 cc) and concentrated to dryness under reduced pressure (2.7 kPa) after filtering off the precipitate. The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 125 cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolving in boiling isopropyl ether (60 cc) to which hexane (30 cc) had been added. The cooled solution is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone (1.2 g) in the form of a white meringue containing 10% of (3aR,7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone; [α]D20 =-181° (c=0.81, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1ccccc1Cl
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To a 50 liter flask was added diethyl o-chlorobenzylmalonate (6067 g, 21.31 mol), glacial acetic acid (1090 mL), and concentrated hydrochloric acid (16,000 mL). The reaction was then heated at reflux for 21 hours and 13 minutes. Additional concentrated hydrochloric acid (1840 mL, 5520 mL total) was added at 3.5, 13.5, and 17 hours into the reflux. The reaction was cooled to 0°±2° C. and the resulting solid was collected by suction filtration and washed with water (4 L). The solid was suspended in water (8 L) and the slurry was stirred for five minutes. The solid was collected by suction filtration and washed with water (20 L). The filtrate was pH 2 and tested positive for chlorine. The solid was then washed seven times in the following manner; the solid was suspended in water (8 L) and stirred for approximately ten minutes. The solid was collected by suction filtration and washed with water (4 L). The filtrate was tested for chloride ion and the pH was recorded. The final filtrate was pH 4.5-5 and tested negative to the presence of chloride ion. A total of 100 liters of water was used to wash the solid. The solid was dried under vacuum at 35±3° C. for 70 hours to give crude β-2-chlorophenylpropionic acid (3653 g, 93.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(O)(=O)C>[O:14]=[C:13]1[NH:15][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH2:18]2)[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]1=2
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1NC2(CCN(C(=O)OCc3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.219 g, 1.00 mmol), benzyl 4-oxo-1-piperidinecarboxylate (0.700 g, 3.00 mmol), p-toluenesulfonic acid monohydrate (0.211 g, 1.10 mmol) and toluene (10.0 mL) was stirred for 2 h at 90° C. Then, acetic acid (10.0 mL) was added, and the mixture was stirred for 1 h at 80° C. After removal of the solvent at reduced pressure, the obtained residue was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with ethyl acetate/dichloromethane (1:1, 10 mL), and the precipitate was collected by filtration to afford the title compound (0.276 g, 64%) as a yellow solid:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.C[O-].[Na+:11]>CO>[Na+:11].[NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH-:8])=[O:7])=[N:2]1
Reactant: NC(=O)c1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [NH-]C(=O)c1nc[nH]n1

Procedure:
A 0.6 g. portion of 1,2,4-triazole-3-carboxamide is added to 5.4 ml. of a solution of 1N sodium methoxide in methanol contained in a test tube at room temperature. The mixture is shaken vigorously. Within about 1/2 to one minute most of the solid dissolves. The mixture is quickly filtered through a sintered glass funnel with vacuum. The light yellow filtrate is allowed to stand and deposits a colorless solid. A portion of methanol is added and the solid is collected, washed with methanol and air dried for one hour yielding 0.3 g. of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19].N#N>CCO.O.C1(C)C=CC=CC=1.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>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=1
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Clc1cc2[nH]ccc2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2cc3cc[nH]c3cc2Cl)cc1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of 5-bromo-6-chloro-1H-indole (5.92 g, 25.7 mmol), sodium carbonate (5.45 g, 51.4 mmol) and (4-ethoxyphenyl)boronic acid (5.12 g, 30.8 mmol) in EtOH/water/toluene (30 mL, each) was degassed with N2 for 5 minutes, treated with tetrakis(triphenylphosphine)palladium (1.8 g, 16.57 mmol) and degassed for an additional 5 minutes. The reaction mixture was heated to reflux under N2 for 16 hours. The reaction mixture was cooled to room temperature, poured into dilute NH4Cl solution (200 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (9-25% EtOAc/petroleum ether) to afford the title compound (6.03 g, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (br, 1 H), 7.50 (s, 1 H), 7.43 (s, 1 H), 7.33 (d, 2 H), 7.15 (m, 1 H), 6.89 (d, 2 H), 6.46 (s, 1 H), 4.02 (q, J=7.00 Hz, 2 H), 1.36 (t, J=7.00 Hz, 3 H).