Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([O:12]C)=[CH:5][CH:4]=1)#[N:2].C([S-])C.[Na+].C(OCC)(=O)C.Cl>CN(C=O)C>[C:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(C#N)c2ccsc12
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)c2sccc12
Temperature: 150 °C
Yield: 99.3 %

Procedure:
To a solution of 4-cyano-7-methoxy benzo[b]thiophene (450 mg, 2.38 mmol, 1 equiv.) in dry DMF (20 mL) was added sodium ethanethiolate (80% technical grade, 1.34 g, ˜13 mmol, ˜5 equiv.) and the reaction mixture was heated at 150° C. for 2 hr. The mixture was cooled to room temperature and ethyl acetate and 1N HCl were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine (3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The acquired material thus obtained was purified via medium pressure liquid chromatography eluting with 30% ethyl acetate/70% hexanes to afford the title compound (414 mg, 99%) as a colorless solid; □H (400 MHz, CD3OD) 6.80 (1H, d, J=8 Hz), 7.47 (1H, d, J=6 Hz), 7.64 (1H, d, J=8 Hz), 7.83 (1H, d, J=6 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 7 h
Yield: 91.7 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro4-hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of conc. H2 SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62 (d, J=8.1, 1H), 7.16 (d, J=7.8, 1H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1H), 3.71 (m, 2H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1H), 1.61 (m, 1H), 1.51 (s, 9H), 1.3 (d, J=6.8, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@H:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: C[C@H](N)c1ccnc2ccccc12
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccnc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(quinolin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 554 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:6]=1)=[O:4].[CH:17]1(B(O)O)[CH2:19][CH2:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:17]2[CH2:19][CH2:18]2)=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:6]=1)=[O:4]
Reactant: OB(O)C1CC1
Reactant: COCCOc1nc(C(=O)OC)ccc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOc1nc(C(=O)OC)ccc1C1CC1
Yield: 142.9 %

Procedure:
Under an atmosphere of nitrogen, a solution of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.2 g, 0.7 mmol), cyclopropylboronic acid (CAN 411235-57-9, 81 mg, 0.9 mmol), palladium acetate (CAN 3375-31-3, 8 mg, 0.037 mmol), tricyclohexylphosphine (CAN 2622-14-2, 0.021 g, 0.07 mmol) and potassium phosphate (0.54 g, 0.20 mmol) in toluene (20 mL) and water (1 mL) was heated to 110° C. for 48 h. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (3×30 mL), washed with brine, dried (sodium sulfate) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 10 g, 5% ethyl acetate in petroleum ether) to yield the title compound (0.16 g, 1 mmol, 93%) as yellow oil; MS (EI): m/e 252.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[CH:10][C:11]=1[NH2:12])=[O:5])[CH3:2].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:13]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)=[CH:10][C:11]=1[NH:12][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1N
Reactant: O=Cc1ccccc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.3 %

Procedure:
47 mg of 4-amino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 2 mL of tetrahydrofuran, to which 21.5 mg of benzaldehyde, 3.1 mg of dibutyltin dichloride and 16.4 mg of phenylsilane were added, and stirred at room temperature for 3 days. For every 24 hours in the meantime, 21.5 mg of benzaldehyde, 3.1 mg of dibutyltin dichloride and 16.4 mg of phenylsilane were each added twice. To the reaction mixture water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) and silica gel thin layer chromatography (chloroform:methanol=20:1) to obtain 3.0 mg of the title compound crude product containing impurities as a light yellow oil. Without further purification, this was used in the next reaction as it was.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C

Procedure:
2-tert-butylphenol (Aldrich, 15.02 g, 15.4 ml, 100 mmol), propargyl bromide (80% in toluene, 14.3 ml, 128 mmol) and potassium carbonate (17.66 g, 128 mmol) were stirred together in acetonitrile (200 mL) for 5 days at ambient temperature. The solvent was removed under reduced pressure, and the residue taken into water and extracted with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9H), 2.48 (t, J=2.37 Hz, 1H), 4.73 (d, J=2.37 Hz, 2H), 6.90-6.98 (m, 2H), 7.15-7.22 (m, 1H), 7.30 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 206 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(Cl)c3)CC12
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-chlorophenylacetic acid (1.19 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (100 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-chlorophenyl)acetyl]-4-perhydroisoindolone (2.2 g) is obtained in the form of white crystals melting at 179° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]2[CH:14]=[N:13][C:12](C(O)=O)=[C:11]([CH3:23])[C:10]3=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[N:1]1([C:7]2[CH:8]=[C:9]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[C:11]([CH3:23])[C:10]3=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)O)ncc2[nH]c3ccc(N4CCCCC4)cc3c12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cc1cncc2[nH]c3ccc(N4CCCCC4)cc3c12
Yield: 32.2 %

Procedure:
2.5 g of 6-piperidino-4-methyl-β-carboline-3-carboxylic acid are heated with 520 mg of copper powder in 50 ml of quinoline for 1.5 hours to 190°-220° C. bath temperature. After distilling off the quinoline in a bulb tube, it is dispersed in ethyl acetate/10% aqueous ammonia. The precipitate that is formed is filtered off and absorptively precipated with ethanol. The combined evaporation residue of the ethanol extraction and the ethyl acetate phase yields 690 mg of 6-piperidino-4-methyl-β-carboline with a 235°-238° C. (decomposition) melting point by crystallization from ethylacetate/diisopropylether.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccsc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 8 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 6, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (8%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1.N12CCCNC1CCCC=C2.C(N(CC)CC)C>C(#N)C>[C:49]([N:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:48][CH2:47]1)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCCCN1CCN(C(=O)c2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: C1=CN2CCCNC2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCN1CCN(C(=O)c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mmol.) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mmol.) of N-hydroxysuccinimide in acetonitrile (15 ml) was added, at room temperature, 1.76 g (9.18 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride. The mixture was stirred for 2 hours. To the reaction system was added a solution of 1.68 g (5.5 mmol.) of 4-(4-aminobutan-1-yl)-1-benzoylpiperazine dihydrochloride, 1.68 g (11.04 mmol.) of 1,8-diazabicyclo[5.4.0]undecene (DBU) and 1.5 ml (10.76 mmol.) of triethylamine in acetonitrile (10 ml). The mixture was stirred for further 2 hours. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate (a small volume of ethanol was also used). The organic layer was washed with a saturated aqueous saline solution and dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a column chromatography (methanol/ethyl acetate 20-30%) to give the object compound as a reddish amorphous product. The yield was 1.25 g (59%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25](O)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:34]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:36]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(cyanomethyl)quinoline-2-carboxylic acid (46.2 mg, 0.128 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (46.6 mg, 0.143 mmol) and HATU (153.3 mg, 0.4032 mmol), DMF (2.00 mL) was added, followed by DIPEA (181.8 mg, 1.406 mmol). The reaction mixture was stirred at room temperature for 15 h, and was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound as a brown solid (65.8 mg, 77%). LCMS calc. for C38H36N7O5 (M+H)+: m/z=670.3. found 670.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].NC(CO)CO.Cl[C:23]1[C:24]([CH2:30][CH3:31])=N[CH:26]=[CH:27][C:28]=1Cl.C(=O)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[N:6][CH:5]=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:14][O:15][CH:26]([C:27]2[CH:31]=[CH:30][CH:24]=[CH:23][CH:28]=2)[O:13][CH2:12]1
Reactant: CCc1nccc(Cl)c1Cl
Reactant: CCc1nccc(NC(CO)CO)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(CO)CO
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=Cc1ccccc1
Product: CCc1nccc(NC2COC(c3ccccc3)OC2)c1Cl

Procedure:
2.3 g (10 mmol) of 5-chloro-6-ethyl-4-(1,3-dihydroxy-2-propylamino)-pyridine (prepared analogously to Example A from 2-amino-1,3-propanediol and 3,4-dichloro-2-ethyl-pyridine) and 5.0 g of benzaldehyde were heated with 2.1 g of p-toluenesulfonic acid hydrate in 40 ml of toluene, using a water separator, until the evolution of water had ended. Working up and purification were carried out analogously to Example A. the chromatography over silica gel (ethyl acetate) gave initially 0.6 g of trans isomer (18.8% of theory), melting point: 139-140° C., and then 2.4 g of cis isomer (75.2% of theory), melting point 119-120° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9]C)=O)=[N:4][S:5][CH:6]=1.O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]1[C:3]([C:7]([NH:12][NH2:13])=[O:9])=[N:4][S:5][CH:6]=1
Reactant: COC(=O)c1nscc1C
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1csnc1C(=O)NN
Temperature: 25 °C

Procedure:
Methyl 4-methyl-3-isothiazolecarboxylate (I128) (57 mg, 0.363 mmol) was dissolved in methanol (3 mL), treated with hydrazine hydrate (0.027 mL, 0.544 mmol) then heated at reflux for 18 hours. Cooled to RT then solvent evaporated, azeotroped with Et2O (3 ml), and evaporated to afford a pale yellow solid of desired product in 57 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)nc(N)n1
Solvent: CC#N
Product: Cc1nc(N)nc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 4.31 g (34.75 mmol) of 2-amino-4,6-dimethylpyrimidine (2) in 150 mL of acetonitrile were added 6.15 g (52.12 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature under argon atmosphere for 3 h. The formed precipitate was filtered and dried to afford the expected product as a white solid: yield 5.93 g (83%). 1H-NMR (CDCl3) δ 5.19 (br, 2H), 2.44 (s, 6H); 13C-NMR (CDCl3) δ 166.28, 160.73, 109.60, 24.70.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:34][C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(Br)s2)cc1

Procedure:
A solution of 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 65, 202 mg, 510 μmol), NBS (91 mg, 510 μmol), and Bz2O2 (6 mg, 26 μmol), in CCl4 (2 mL) was heated to reflux for 16 h. After removal of the solvent, the residue was partitioned between EtOAc (30 mL) and H2O (30 mL). The organic extracts were washed with saturated aqueous NH4Cl (30 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (CH2Cl2-EtOAc, 2:3) gave the title compound: RTA=3.50 min; m/z (ES+)=516.2 [M+MeCN+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCC.CN(C=O)C>[C:8]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cncn2)cc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 13.8 g, 345 mmol) was washed with hexane and suspended in DMF (150 ml). At an ice bath temperature, 1,2,4-triazole (total; 20.7 g, 300 mmol) was added thereto in four divisions. After stirring for 30 minutes, to the mixture was added tritylchloride (total; 83.7 g, 300 mmol) in seven divisions and additionally added DMF (50 ml). After stirring for 1.5 hours at room temperature, to the reaction mixture was added water (600 ml). The precipitated crystal was collected by filteration, washed with water, dissolved in CHCl3 (800 ml) and dried. The solvent was evaporated. The obtained residue was chromatographed on silica gel (ethylacetate:CHCl3=1:2, v/v). The fraction of the objective was concentrated to give 1-trityl-1H-1,2,4-triazole (43.9 g). Yield: 47%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1[CH2:12][CH2:11]OCC1.[CH:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH:25]=[CH:26]/[CH2:27]C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:27]=[CH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[CH:14]=[CH:13]/[CH2:11][CH3:12]
Reactant: CC/C=C\C=C/CCCCCCCCCC=O
Reactant: C1COCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: C=CCCCCCCCCC/C=C\C=C/CC

Procedure:
(Z,Z)-1,12,14-heptadecatriene (TRIENE) was synthesized conveniently from Wittig Salt and aldehyde in aqueous dioxide-potassium carbonate heterogeneous medium (Lechat 1982). A mixture of 3.57 g (0.01 mol) of methyl triphenylphosphonium bromide (Alfa Inorganics), 1.7 g (0.14 mol) of potassium carbonate, 10 ml of 1,4-dioxane, 0.15 ml of water and 2.36 g (0.01 mol) of (Z,Z)-11,13-hexadecadienal (AL. Albany International) was prepared in a 100 ml round bottomed flask equipped with a magnetic stirrer, thermometer and reflux condenser. The mixture was heated to reflux at 105-110° with stirring while aliquots of 15 ul were withdrawn periodically and partitioned between 1 ml of H2O and 1 ml of hexane. Analysis by gas-liquid chromatography, showed 66,70 and 99% triolefin and 30%, 26% and 1% starting aldehyde at 1.1 and 2.2 and 17 hr, respectively. More potassium carbonate (1.7 g) was added at 212 hr to drive the reaction to completion. The reaction mixture was cooled and extracted 3 times with 25 ml of hexane, then the organic layer was extracted with water, dried and the solvent removed to leave 1.8 g of yellow oil and a few crystals of triphenylphosphine oxide. The oil was taken up in hexane and passed through a 1×45 cm column of silica gel (60-200 mesh, Baker) with hexane, to yield 1.7 g (73% yield) of clear oil.