Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[O:34][C:33]([C:35](Cl)=[O:36])=[CH:32][CH:31]=1)#[N:29].CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:33]3[O:34][C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)=[O:36])=[C:16]([N:21]3[C:22]([CH3:27])=[CH:23][CH:24]=[C:25]3[CH3:26])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 19 %

Procedure:
Using a procedure similar to Example 4, step (c), 4-[4-amino-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.8 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (25 mg, 0.16 mmol) in the presence of DIEA (276 mg, 1.7 mmol) to afford 14.9 mg (38%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 400 MHz): 8.43 (d, 1H, J=9.3 Hz), 7.25 (s, 1H), 7.10-7.13 (m, 2H), 7.03-7.06 (m, 1H), 6.89 (s, 1H), 6.06 (s, 2H), 3.62-3.61 (m, 4H), 3.18-3.17 (m, 4H), 1.96 (s, 6H), 1.48 (s, 9H); Mass spectrum (ESI, m/z): Calcd. for C27H31N5O4, 390.1 (M-BOC+2H), found 390.1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6].O=S(Cl)Cl.[F:16][C:17]1[CH:18]=[C:19]([C@@:30]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=1>ClCCCl>[F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([NH:38][C@@:30]([C:19]1[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=[C:17]([F:16])[CH:18]=1)([C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:6]
Reactant: CC(C)(CC(F)(F)F)C(=O)O
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 4,4,4-trifluoro-2,2-dimethylbutanoic acid (30 mg, 0.176 mmol) in DCE (1 mL) was added SOCl2 (21 mg, 0.176 mmol) and the resulting mixture was refluxed for 2 h. After cooling to room temperature, TEA was added (82 uL, 0.59 mmol), followed by the addition of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine, prepared as described in Procedure 3, 4, 5 and 6, (25 mg, 0.059 mmol). The reaction mixture was heated to reflux overnight, concentrated and the residue was purified by preparative HPLC (Axia column, 30×100 mm, 40 mL/min, 40-100% ACN/H2O/0.1% TFA over 12 min) to give (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide (Example 266) as a brownish oil (8 mg, 24% yield). LCMS: RT=2.13 min [M+H] 578.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 1.28 (s, 6H), 2.21-2.51 (m, 2H), 3.77 (ABqt, J=13 Hz, 2H), 5.83 (t, J=53 Hz, 1H), 6.37 (s, 1H), 6.65-6.74 (m, 2H), 6.75-6.95 (m, 3H), 6.94-7.09 (m, 4H), 7.09-7.31 (m, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.[C:12]1(C)[C:13](S(O)(=O)=O)=[CH:14][CH:15]=[CH:16][CH:17]=1.C=CCCCC>>[C:1]([O:8][CH2:14][CH2:13][CH2:12][CH2:17][CH2:16][CH3:15])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CC(=O)CCC(=O)O
Solvent: C=CCCCC
Solvent: O=CO
Product: CCCCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 2 mmoles of levulinic acid and 0.2 mmoles of formic acid. 3 wt. % toluene sulfonic acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-hexene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-hexene. After cooling, the organic phase is separated. A mixture of hexyl formate and hexyl levulinate is formed as product.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][CH2:17]2)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCNCCN1CCCN1CCC2(CC2)[C@H](O)C1
Agent: Cl
Product: O=C1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)CCN1CCCN1CCC2(CC2)[C@H](O)C1

Procedure:
In analogy to the procedure described in example 5, 4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride (US 2007249589, described as 4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride) and 3,4-dichlorophenyl isocyanate gave after separation with flash chromatography (silicycle SiO2, dichloromethane/methanol 95:5 to 4:1) 43% of the title compound as white solid. MS: 469.3 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].O1CCOCC1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].O>[CH2:21]([O:28][C:29]([N:3]([CH2:1][CH3:2])[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN[C@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
2.9 g (0.015 mole) of N-ethyl-D-phenylalanine (Example 3, Step A) are dissolved in 22.5 ml of 2N sodium hydroxide, 10 ml of dioxane are added, the mixture is cooled to 5° to 10° C., then 2.5 ml (about 0.017 mole) of benzyloxycarbonyl chloride are added and the reaction mixture is stirred for 3 hours at cooling. Subsequently it is diluted with 40 ml of water and extracted with 30 ml of a mixture of diethyl ether-petroleum ether-1:1, when a three-phase system is formed. The two lower phases are again extracted with 30 ml of diethyl ether, then the combined diethyl ether layers are washed with 20 ml of water. The aqueous layers are combined and acidified with N sulfuric acid to pH 2. The separated product is extracted three times with 30 ml of ethyl acetate. The ethyl acetate layers are combined, washed twice with 20 ml of water, dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of max. 40° C. at 15 to 20 millibars. Yield 2.7 g (55%) of an oil.
Reaction SMILES: O.[ClH:2].Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:17]>CN(C)C=O>[ClH:2].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[C:9]1[CH:10]=[C:11]([NH:12][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C2=NCCN2)c1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(NC(=O)Nc2cccc(C3=NCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 3-(4,5-dihydro-1H-imidazol-2-yl) aniline dihydrochloride monohydrate (stored with 4 A molecular sieves, 48 mg, 0.19 mmol) and 4-ethoxyphenyl isocyanate (33 mg, 0.20 mmol) in dimethylformamide (2 ml) was stirred at room temperature overnight. After removal of the solvent, water (2 ml) was added and the resulting precipitate was collected (18 mg, 64% yield) by filtration. 1H NMR (600 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.12 (br s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.52 (t, 1H, 8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.35 (d, 2H, J=7.2 Hz), 6.86 (d, 2H, J=7.2 Hz), 3.98 (s, 4H). MS: m/z Calcd 324.4 Found MH+ 325.5
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH2:18]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:18][C:14]2[O:13][CH:17]=[CH:16][N:15]=2)[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: Nc1ncco1
Product: COC(=O)c1cc(C)nc(Nc2ncco2)n1
Yield: 22 %

Procedure:
The title compound is prepared in 22% yield (83 mg, a pale yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (300 mg, 1.6 mmol) and oxazol-2-amine (200 mg, 2.4 mmol) by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [Li][C:2]1([Si](C)(C)C)C2N=CC(C)=CC=2CCC1.C(=O)=O.[CH3:20][C:21]1[CH:22]=[N:23][C:24]2[C:25]([Si](C)(C)C)([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=1.[Li+]>>[CH3:2][O:33][C:31]([CH:25]1[C:24]2[N:23]=[CH:22][C:21]([CH3:20])=[CH:30][C:29]=2[CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21
Reactant: Cc1cnc2c(c1)CCCC2(C(=O)[O-])[Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Product: COC(=O)C1CCCc2cc(C)cnc21

Procedure:
8-Lithio-5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline, prepared as in Example 3, is blown over onto ether at 0° C. through which a vigorous stream of CO2 gas is being passed. After the addition the resulting solid, lithium 5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline-8-carboxylate, is removed by filtration. This is then dissolved in methanol (200 ml) and the solution treated with HCl gas to excess and heated at reflux for 4 hours. The solvent is removed in vacuo and the residue dissolved in water (50 ml), made alkaline with 2N NaOH and extracted with chloroform. The extracts are dried, evaporated and the residue distilled to give the title compound as a pale yellow oil bp 120°/0.25 mm.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([Cl:16])=[O:15].N1C=CC=CC=1>O1CCCC1>[Cl:16][S:14]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[O:15]
Reactant: CC(C)OC(=O)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)OC(=O)N(c1ccccc1)S(=O)Cl
Yield: 61.1 %

Procedure:
Eighteen grams isopropyl phenylcarbamate (~0.1 mol) and 14.0 g thionyl chloride (0.12 mol) were dissolved in 50 ml dry tetrahydrofuran and protected from moisture by a calcium chloride tube. Eight grams pyridine (0.1 mol) were added dropwise while the mixture was stirring at a water bath temperature (15°-20° C.). After the addition of pyridine was completed, the mixture was stirred for 12 hours at room temperature. Pyridine hydrochloride was filtered and the solvent was removed under vacuum. The concentrated residue was diluted with hexane and filtered. The hexane was removed under vacuum and the residue was distilled, giving 16.0 g of product distilling at 113-115/0.08 mm. NMR spectrum of the product in chloroform-d-TMS gave the following absorptions: δ7.6-7.2 (m, 5H, phenyl protons), δ5.5-4.9 (m, 1H, CH) and δ1.4-1.3 (d, 6H, C(CH3)2).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: O=Cc1ccc2occ(Br)c2c1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3occ(Br)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 3-Bromo-benzofuran-5-carbaldehyde (intermediate 58) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [Na].[O:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:18](OCCC(C)C)=[O:19].Cl>C(O)C>[OH:19][N:18]=[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:16]#[N:17]
Reactant: N#CCc1ccccc1Oc1ccccc1
Reactant: CC(C)CCON=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
To anhydrous ethanol (15 ml) was dissolved sodium (0.55 g, 0.024 mole) and a mixture of 2-phenoxyphenylacetonitrile (4.18 g, 0.02 mole) and anhydrous ethanol (3 ml) was added dropwise to the mixture below 0° C. over 7 minutes. Isoamyl nitrite (3.51 g, 0.03 mole) was further added dropwise to the mixture below 0° C. over 10 minutes, followed by stirring at room temperature for 24 hours. After completion of the reaction, 5% hydrochloric acid was added to the reaction mixture, which was extracted with ether and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-hydroxyimino-2-phenoxyphenylacetonitrile (4.53 g, yield: 95.1%) as crystals having a low melting temperature.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(N=[N+]=[N-])nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=3:1:1) by a procedure similar to that of Example 120 (4%). 1H NMR (CDCl3): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1)=[O:19]
Reactant: NCc1ccccc1F
Reactant: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (271 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the reaction mixture was stirred for lh. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. The crude material was triturated with 2:2:1 water/CH3CN/DMSO and the resultant white solid filtered off. Repetitive concentration and trituration of the filtrate in the same manner gave cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide (F) (230 mg, 60%) as a white solid. The (F) compound was stirred in 1M HCl/ether (10 ML) for 1 h and concentrated to give the HCl salt of Ex. 7 (250 mg): 1H NMR (400 MHz, CD3OD) δ 7.50 (br s 2H), 7.35-7.25 (m, 2H), 7.22-7.05 (m, 4H), 4.43 (s, 2H), 2.92 (d, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.93 (m, 2H), 1.60 (m, 6H); mass spectrum m/z 366 [(M+H)+; calcd for C22H25N3OF: 366].
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[S:27][CH2:28][CH2:29][C:30](O)=[O:31].[NH4+].[OH-]>C1COCC1>[Cl:39][C:35]1[CH:34]=[C:33]([CH:26]2[C:7]3[CH:8]=[C:9]([CH:12]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[C:13]4[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=4)[CH:10]=[CH:11][C:6]=3[NH:5][C:30](=[O:31])[CH2:29][CH2:28][S:27]2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(SCCC(=O)O)c2cccc(Cl)c2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCCC(=O)N2
Yield: 3.5 %

Procedure:
Thionyl chloride (1 ml) was added slowly to a mixture of intermediate (22) (0.00456 mol) in THF (15 ml). The mixture was stirred and refluxed for 2.5 hours, poured out on ice and NH4OH and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried in vacuo. The residue was recrystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 0.08 g (3%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,3,4,6-tetrahydro-2H-5,1-benzothiazocin-2-one, mp. 199° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC1(C)CC(CCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 50 °C
Yield: 63.3 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate, (0.2 g, 0.571 mmol) and anhydrous potassium carbonate (0.316 g, 2.284 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.152 g, 0.685 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and then extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. DMSO:MeOH (1:1) was added to the residue and the resulting precipitate was collected by filtration, washed with methanol and dried in vacuo to give the title compound as a white solid (136 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:11][C:10]=2[CH3:22])O1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=3[CH3:45])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][CH:33]=2)[CH:28]=[N:27][N:26]=1>>[CH3:45][C:44]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][CH:32]=1)[C:25]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[CH:11][C:10]=1[CH3:22])=[N:26][N:27]=[CH:28]2
Reactant: Cc1cc(S(=O)(=O)C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Product: COC(=O)c1ccc(C)c(-c2ccc3c(-c4ccc(S(=O)(=O)C(F)(F)F)cc4C)nncc3c2)c1

Procedure:
Methyl 4-methyl-3-(1-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)phthalazin-6-yl)benzoate was prepared according to the procedure described in Example 223, using 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)-1,3,2-dioxaborolane and methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate as starting materials. MS (ESI, pos. ion) m/z: 500.9 (M+1).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:16][CH:13]1[CH2:14][CH2:15][CH:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH2:11][CH2:12]1
Reactant: CC#CCO
Reactant: CC1CCC(c2nc(S(C)(=O)=O)ns2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCC(C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
400 mg of 3-methylsulfonyl-5-(4-methylcyclohexyl)-1,2,4-thiadiazole and 129 mg of 2-butyn-1-ol were dissolved in 3 ml of N,N-dimethylformamide, 80 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 258 mg of 5-(4-methylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (12)).
Reaction SMILES: [C:1]([O-])(=O)CC.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].IC>CN(C=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([C:30]2[N:34]([CH3:1])[N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Reactant: CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(=O)N(c1ccccc1)C1(c2nnnn2C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a stirring mixture of 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (18.9 g, 40.7 mmol) and DMF (120 ml), NaH (2.4 g,m 100 mmol) was added. The mixture was stirred at room temperature for 30 minutes. To the resulting brown solution, iodomethane (15 g, 106 mmol) was added slowly. It was stirred for 30 minutes and poured onto H2O (400 ml). The mixture was extracted with CH2Cl2 (2×250 ml). The CH2Cl2 solution was washed with H2O (4×400 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, 1% MeOH/CH2Cl2) to give 1-benzyl-4-(1-methyl-1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidine (4.58 g, 11.3 mmol) as a colorless viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHZ, CDCl3) δ 0.834, (t, 3H, CH3CH2CO), 1.789 (q, 2H, CH3CH2), 3.334 (s, 2H, phCH2), 4.435 (s, 3H, tetrazolyl CH3), 7.15 to 7.47 (m's, 10H, phenyl H's), and 1-benzyl-4-(2-methyl-2H-tetrazol-5-yl)-4-(N-phenyl)propionamido)piperidine (2.75 g, 6.8 mmol) as a viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHz, CDCl3) δ 0.830 (t, 3H, CH3CH2CO), 1.810 (q, 2H, CH3CH2), 3.402 (s, 2H, phCH2), 4.369 (s, 3H, tetrazolyl CH3), 7.20 to 7.54 (3m's, 10H, phenyl H's). ##STR31##