Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.C[O-].[Na+].C[CH2:29][O:30]C(C)=O.O>CN1C(=O)CCC1.[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[O:30][CH3:29]
Reactant: CCOC(C)=O
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: [Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 100 °C

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), sodium methoxide (70 mg), CuI (5 mg) in NMP (1.0 ml) was heated at 100° C. for 2.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE to give 5-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (58 mg).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Cl)(=[O:3])[CH3:2].[CH:25](=[O:37])[C:26]1[CH:36]=[C:33]([O:34][CH3:35])[C:31]([OH:32])=[C:28]([O:29][CH3:30])[CH:27]=1>CC(C)=O.[OH-].[K+].O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:32][C:31]1[C:33]([O:34][CH3:35])=[CH:36][C:26]([CH:25]=[O:37])=[CH:27][C:28]=1[O:29][CH3:30])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Reaction time: 18 h

Procedure:
A solution of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride (18.3 g, 50 mmol) in acetone (100 ml) was added to a solution of syringaldehyde (9.1 g, 50 mmol) in 1M potassium hydroxide solution (100 ml). The mixture was then stirred for 18 h and then diluted with water. The precipitated crystalline solid (10.8 g, 42%) was then filtered off, washed well with water and recrystallised from acetone-water water to give the title compound, m.p. 222°-225°, [α]D +3° (c 0.9, CHCl3)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]([C:18]2[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[S:21][C:22]=2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH2:17])[CH:13]=[CH:12][CH:11]=1>CO.[Pd]>[CH3:8][O:9][C:10]1[N:15]=[C:14]([CH:16]([C:18]2[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[S:21][C:22]=2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:17])[CH:13]=[CH:12][CH:11]=1
Reactant: C=C(c1cccc(OC)n1)c1c(CCN(C)C)sc2ccccc12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cccc(C(C)c2c(CCN(C)C)sc3ccccc23)n1
Reaction time: 2.5 h

Procedure:
The TFA salt of (2-{3-[1-(6-methoxy-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (190 mg, mmol) was dissolved in MeOH (12 mL) and a catalytic amount of 10% Pd/C was added. The reaction was stirred under 1 Atm of H2 for 2.5 hours, filtered over celite, washed with dichloromethane, concentrated in vacuo and purified by mass triggered preparative HPLC to give (2-{3-[1-(6-methoxy-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 15-2). MH+=341.0, tR=5.2 min.
Reaction SMILES: BrC1C=CC([C@](CC=O)(C(O)CCCCCCCCCC(C)C)C([O-])=O)=CC=1.[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH3:35])=[O:33].O[Li].O.C1CCC(NC2CCCCC2)CC1.BrC[C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69]>>[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH2:35][C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69])=[O:33]
Reactant: COC(=O)C[C@H](O)CCCCCCCCCCCC(C)C
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)CCCCCCCCCC(O)[C@](CC=O)(C(=O)[O-])c1ccc(Br)cc1
Agent: [Li]O
Solvent: O
Product: CC(C)CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)c1ccc(Br)cc1
Yield: 89.8 %

Procedure:
In a manner similar to the synthesis of 116, compound 115 (960 mg, 3.2 mmol) was hydrolyzed with LiOH.H2O (202 mg, 4.8 mmol), recrystallized by refluxing with DCHA (0.76 mL, 3.84 mmol) and protected by reacting with 2,4′-dibromoacetophenone (979 mg, 3.52 mmol) to afford 118 as an amorphous solid (1.39 g, 90%). Rf=0.35 (DCM); [α]25D=−1.2° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.74 (d, 2H, J=8.4 Hz, aromatic), 7.60 (d, 2H, J=8.4 Hz, aromatic), 5.39 (d, 1H, J=16.5 Hz, CH′2a), 5.29 (d, 1H, J=16.5 Hz, CH′2b), 4.08 (m, 1H, H-3), 2.65 (dd, 1H, J2a,2b=15.0 Hz, J2a,3=3.0 Hz, H-2a), 2.54 (dd, 1H, J2a,2b=15.0 Hz, J2b,3=9.0 Hz, H-2b), 1.58-1.46 (m, 3H, H-4, H-15), 1.24-1.13 [m, 20H, H-(5-14)], 0.83 (d, 6H, J15,16=6.6 Hz, H-14). 13C NMR (75 MHz, CDCl3): δ 191.60 (C═O), 171.86 (C═O), 132.49-129.24 (m, aromatic), 68.38 (C-3), 65.74 (C-2′), 41.96 (C-2), 39.00 (C-14), 36.54 (C-4), 22.61 (C-16). HR MS (m/z) calculated for C25H39BrO4 [M+Na]+, 505.1924. found, 505.1160.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and glycine benzylester p-toluene sulfonic acid salt (1.0 g, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was dropwise added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling, and next, overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus dried solution was distilled off an under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-glycine benzylester material (1.5 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g, 1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in 30 mL dichloromethane and cool to 0° C. Treat the reaction mixture with benzoyl chloride (276 mg, 1.96 mmol) and stir overnight during which the temperature was allowed to warm to room temperature. Concentrate to residue and chromatograph the residue on silica gel eluting with 0.5% MeOH in CHCl3 to give the title compound as a solid: ISMS 410 (M+1); 1H NMR (CDCl3) 7.86–7.85 (m, 2H), 7.79 (s, 1H), 7.72–7.68 (m, 2H), 7.60–7.57 (m, 2H), 7.46–7.42 (m, 1H), 7.4–7.36 (m, 3H), 7.13–7.11 (d, 1H), 6.89–6.88 (m, 1H), 3.88–3.84 (t, 2H), 3.00–2.97 (t, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][C:22]=1[CH3:28]>>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][C:22]=1[CH3:28]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1cc(S)ccc1Br
Product: Cc1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-bromo-3-methyl-thiophenol.
Reaction SMILES: ON1C(=O)CCC1=O.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[NH:37][CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[N:37]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCc1nc2c([nH]1)CC(C(=O)OC)NC2
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c([nH]1)CC(C(=O)OC)N(C(=O)OCc1ccccc1)C2
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
N-Hydroxysuccinimide (0.69 g) and triethylamine (0.6 g) are dissolved in dry dimethylformamide (5 ml), and thereto is added dropwise benzyloxycarbonyl chloride (1.02 g) under ice-cooling. The mixture is stirred for 10 minutes, and thereto is added triethylamine (2.0 g). To the mixture is further added a solution of methyl 2-n-butyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate hydrochloride (1.55 g) in dimethylformamide (5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and thereto are added water and chloroform. The aqueous layer is extracted with chloroform, and the extract is combined with the chloroform layer, dried, and evaporated under reduced pressure to remove the solvent. The resulting oily residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give methyl 2-n-butyl-5-benzyloxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (1.21 g) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: CCCCCCCI
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
In 32 ml of water and 32 ml of ethanol, 27.2 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 9.0 g of sodium hydroxide were added. To this solution, 45.2 g of 1-iodoheptane was added, and the mixture was stirred at 60° C. for 2 hours. After cooling, water was added to the mixture and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 36.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:2]=1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cncc(CNCCN2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCN1CCNCC1)Cc1cccnc1

Procedure:
1-(2-[3-pyridylmethylamino]-ethyl)-piperazine (2.20 g, 10 mmol) is dissolved in 20 mL of dioxane:water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine (1.951 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: C(=N[NH:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]([CH3:33])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:36]([O:35][C:30]([C:31]1[NH:15][C:16]2[C:17]([CH:33]=1)=[C:18]([C:26]([CH3:27])([CH3:28])[CH3:29])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:23])[CH3:24])[CH:21]=2)=[O:34])[CH3:37]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(C)c1cc(NN=C(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2c(C(C)(C)C)cc(C(C)(C)C)cc2[nH]1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
N-Benzhydrylidene-N′-(3,5-di-tert-butyl-phenyl)-hydrazine (617 mg, 1.6 mmol) was dissolved in ethanol (12 ml). Then, ethyl pyruvate (212 μl, 1.9 mmol) and p-toluene sulfonic acid monohydrate (914 mg, 4.8 mmol) were added thereto. This was heated and stirred at 150° C. by microwave under a nitrogen atmosphere for one hour. After cooling it to room temperature, the reaction mixture was combined with water and an aqueous solution saturated with sodium bicarbonate. The product was extracted into ethyl acetate. The organic layer was isolated, and washed with an aqueous solution saturated with sodium chloride, and dried over magnesium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=100/5). Thus, 4,6-di-tert-butyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a brown solid (268 mg, 56%).
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[CH2:14]1[O:42][C:41]2[CH:40]=[CH:39][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][C:27]([C:31]5[CH:36]([CH3:37])[S:35][C:34](=[O:38])[NH:33][N:32]=5)=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:16]=2[O:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([N:33]1[N:32]=[C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]([C:19](=[O:20])[C:18]2[CH:39]=[CH:40][C:41]4[O:42][CH2:14][O:15][C:16]=4[CH:17]=2)[CH2:22][CH2:23][CH2:24]3)[CH:36]([CH3:37])[S:35][C:34]1=[O:38])=[O:11]
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1SC(=O)N(C(=O)C2CC3CCC2(C)C3(C)C)N=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
A solution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene chloride is added dropwise at 0°, with stirring, to a suspension of 48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene chloride to which 20 ml of triethylamine have been added, and the reaction mixture is stirred for 4 hours. It is then washed with dilute hydrochloric acid and subsequently with bicarbonate solution. The organic phase is separated off and worked up in conventional manner to give 3-[(-)-camphanoyl]-5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 4- tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as a mixture of diastereoisomers, m.p. 216°-217° .
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:18]1([CH2:17][CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCC1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(-c2cn(CCN3CCCC3)cn2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (20 mg, 0.12 mmol), 1-(2-chloroethyl)pyrrolidine hydrogen chloride (34 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) in 2 mL DMF was heated at 90° C. for 2 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-100%). [M+H] Calc'd for C15H17N5, 268. Found, 268.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2ccnn2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 24.5 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84 mmol) and potassium carbonate (47 mg, 0.34 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20, 56 mg, 25%) which was obtained as a white solid. MS: m/e 401.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1ccc(CCl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc(C)cn4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture allowed to cool, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 76.9%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH3:14][N:15]([CH3:35])[C:16]([C@@H:18]1[C@H:23]([NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:32])[C:26]=2[NH2:33])[C@@H:22]2[CH2:34][C@H:19]1[CH:20]=[CH:21]2)=[O:17].C([O-])(=O)C.[NH4+]>>[CH3:14][N:15]([CH3:35])[C:16]([C@@H:18]1[C@H:23]([NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]3[NH:32][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:33][C:26]=23)[C@@H:22]2[CH2:34][C@H:19]1[CH:20]=[CH:21]2)=[O:17]
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5 %

Procedure:
In a similar fashion to Compound LXXXVII 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (69.84 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (93.35 mg, 0.2901 mmol and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 7.35 mg (5%) of the title compound. (300 MHz, DMSO-d6) 13.50 (s, 1H), 7.94 (s, 1H), 6.67 (s, 1H), 6.38 (m, 2H), 5.12 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 3.02 (d, J=9 Hz, 1H), 2.94 (s, 3H), 2.86 (m, 4H), 2.82 (s, 1H), 2.11 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.42 (d, J=8 Hz, 1H). MS=517 (M+H), HPLC: 2.96 min. (G Method)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(OC(C)(C)C)=O>CCCCCC.CCOC(C)=O>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:19][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2

Procedure:
Use a method similar to the General Procedure 4-3, using 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (277 mg, 0.94 mmol) and N-(tert-butoxycarbonyl)ethanolamine (244 mg, 1.51 mmol) to give, after chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1), the desired intermediate (392 mg, 95%). MS (ES+) m/z: 337 (M+H−Boc)+.