Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[CH:48]1[C:55]2[C:54]([CH3:56])=[N:53][N:52]([CH2:57][CH3:58])[C:51]=2[C:50](=[O:59])[N:49]1[C:60]1[CH:61]=[C:62]([CH3:70])[C:63]2[N:64]([C:66]([CH3:69])=[N:67][N:68]=2)[CH:65]=1>CCCCCCC.CCO.CO>[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C@@H:48]1[C:55]2[C:54]([CH3:56])=[N:53][N:52]([CH2:57][CH3:58])[C:51]=2[C:50](=[O:59])[N:49]1[C:60]1[CH:61]=[C:62]([CH3:70])[C:63]2[N:64]([C:66]([CH3:69])=[N:67][N:68]=2)[CH:65]=1
Reactant: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)C2c1ccc(F)cc1F
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CO
Solvent: CCCCCCC
Solvent: CCO
Product: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)[C@@H]2c1ccc(F)cc1F

Procedure:
The title compound (34 mg, 48% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralpak AD-H, 20×250 mm; mobile phase: heptane/EtOH/MeOH 80:10:10; flow: 12 mL/min; temperature: 38° C.; detection UV: 220 nm) of the racemic mixture of 4-(2,4-difluorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-ethyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 181).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[CH2:15]1[C:18]2([CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH:24]=[CH2:25])[CH2:19]2)[CH2:17][NH:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:16]2[CH2:17][C:18]3([CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH:24]=[CH2:25])[CH2:19]3)[CH2:15]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CC(=O)N1CCC2(CNC2)C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCC2(C1)CN(C(=O)CNc1cc(Cl)c(Cl)cc1O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
The mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (47 mg, 0.2 mmol), 1-(2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one (40 mg, 0.2 mmol), EDCI.HCl (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol) and Et3N (0.61 mg, 0.6 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (13 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H), 6.78 (s, 1H), 6.60-6.50 (m, 2H), 6.13 (dt, J=2.4, 16.4 Hz, 1H), 5.67 (dd, J=2.4, 10.4 Hz, 1H), 5.19 (dd, J=5.2, 10.0 Hz, 1H), 4.16-4.07 (m, 2H), 3.90-3.83 (m, 2H), 3.75-3.72 (m, 3H), 3.61-3.52 (m, 2H), 3.42-3.39 (m, 1H), 2.16-2.13 (m, 1H), 2.06-2.03 (m, 1H). ESI-MS m/z: 382.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([C:24](=[CH:27]NC2C=CC=CC=2)[C:25]#[N:26])=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:27][C:24]=1[C:22](=[O:23])[C:21]1[CH:35]=[CH:36][CH:37]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: NNc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylaminoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2—3%MeOH/CH2Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:17](F)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (CAS number 72537-17-8; 1.44 ml, 10.98 mmol), DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.N[C@H](C)[CH2:32][OH:33]>CCO>[OH:33][CH2:32][C@H:3]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)[CH3:2]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: C[C@@H](N)CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](CO)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethyl-1H-pyrimidine-2,4-dione (Intermediate A step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (R)-2-aminopropan-1-ol (45 mg, 0.59 mmol) (commercial) were combined in EtOH (2 mL). The mixture was heated at 100° C. under microwave irradiation for 1 hour. The solvent was evaporated under reduced pressure. The solid residue dissolved in DCM and water and extracted (×3). The combined organic phases were washed with water, passed through a hydrophobic frit and evaporated under reduced pressure to afford the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15].[CH3:16][O-:17].[Na+].CO>[Cu](Br)Br.O>[CH3:16][O:17][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15]
Reactant: C[O-]
Reactant: Cc1cc(C)c2c(c1Br)OC(C)(C)C2=O
Agent: Br[Cu]Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)cc(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 7-bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (2.90 g, 10.8 mmol) synthesized in Reference Example 67, copper bromide (1.86 g, 13.0 mmol) and 28% sodium methoxide/methanol solution (60 mL) was stirred under heated reflux for 15 hours. After cooled to room temperature, the reaction solution was poured into water and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 99:1 to 94:6) to give 1.18 g of the title compound (yield: 50%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31].CO>CC(C)=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:7])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(SC)cc1
Reactant: O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate (0.214 g.; 0.001 mole) in 3 ml. of water is added dropwise to 5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid (0.352 g.) (0.001 mole) in 25 ml. methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a sufficiently small volume that causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° to give 5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 200.5°-203.5°).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)([O-:10])=[O:9]
Reactant: O=C1CNCCN1
Reactant: O=[N+]([O-])c1nccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1CN(c2nccnc2[N+](=O)[O-])CCN1
Reaction time: 20 h
Yield: 54.7 %

Procedure:
A solution of 2-chloro-3-nitropyrazine (9.1 g, 57 mmol) in chloroform (100 ml) was added dropwise over 45 minutes to a cooled solution of piperazine-2-one (5.71 g, 57 mmol) and triethylamine (8.0 ml, 57 mmol) in isopropanol (120 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. The precipitate was removed by filtration and recrystallized from methanol-ethyl acetate-hexane to give 6.96 g (54.7%) of product, m.p. 178°-179°.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH:11]([CH:13]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:14](OCC)=O)=[O:12]>CO>[N+:1]([NH:4][C:5]1[NH:7][C:11](=[O:12])[C:13]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[CH:14][N:6]=1)([O-:3])=[O:2]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1

Procedure:
Nitroguanidine (4.7 g) was added to a solution of sodium methoxide (prepared from 1.15 g sodium) in methanol (50 ml) and the mixture was boiled under reflux for 45 minutes. Ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (10.7 g) was added and the mixture was refluxed for 34 hours and evaporated to a residue. This residue was dissolved in water and the solution was extracted with chloroform (subsequently discarded). The aqueous solution was adjusted to pH 5 with acetic acid, and the solid which precipitated out was filtered off to give 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 183.5-186°.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][CH2:7][C@H:8]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[OH-].[Li+].C(OCC)(=O)C>O1CCOCC1.O>[C:21]([O:20][C:18]([CH2:17][NH:16][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][O:6][CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)COC[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN[C@@H](COCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 56 h
Yield: 68.7 %

Procedure:
((2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropoxyl)-acetic acid ethyl ester (0.60 g, 1.71 mmol) was dissolved in dioxane (5 mL). A solution of lithium hydroxide (0.05g, 2.20 mmol) in water (2 mL) was added. The solution was stirred at room temperature for 56 hours. Ethyl acetate (10 mL) and water (2 mL) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic layers were extracted with 1 N sodium hydroxide solution (20 mL). The combined aqueous phases were acidified with a 1M sodium hydrogensulfate solution (pH 2) and extracted with ethyl acetate (2×20 mL). These ethyl acetate layers were combined and dried over magnesium sulfate. The solvent was removed in vacuum to give 0.38 g of crude ((2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropoxy)acetic acid, which was used for the following steps.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)ncc1Br
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, 100 mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (1400 mL), washed with 1N NaOH (3×200 mL) and NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99%). LCMS (m/z): 188.0/190.0 (MH+). 1H NMR (CDCl3): δ 8.22 (s, 1H), 5.02 (bs, 2H), 2.44 (s, 3H).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O[CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[N:15]([CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)=[N+:16]=[N-:17]
Reactant: OCc1csc2cncn12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: [N-]=[N+]=NCc1csc2cncn12
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Diphenylphosphoryl azide (0.259 ml) and 0.157 ml of 1,8-diazabicyclo[5,4,0]-7-undecene were added to suspension of 154 mg of 3-hydroxymethylimidazo[5,1-b]thiazole in 2 ml of toluene. The mixture was stirred at room temperature for 30 hr. Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to give 156 mg of 3-azidomethylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]=[S:13].[N:14]#[C:15][NH2:16].C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)Cl>[C:15]([NH:16][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[S:13])#[N:14]
Reactant: Cc1[nH]cnc1CSCCN=C=S
Reactant: N#CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]cnc1CSCCNC(=S)NC#N
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A solution of 2-(5-methylimidazol-4-ylmethylthio)ethylisothiocyanate [obtained from its hydrochloride (4.17 g)] in CHCl3 (20 ml) was added to a solution of cyanamide (1.05 g) and DBU (3.80 g) in CHCl3 (50 ml) and stirred overnight. After concentration, the residue was dissolved in water (30 ml) and washed with ether, decolorized with charcoal and acidified to pH 5 with 10% HCl under ice-cooling. The precipitate was filtered, washed with water and dried to give N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea(mono-hydrate, 3.57 g). Yield 78.1%, m.p. 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39]>CN(C=O)C>[ClH:1].[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@H:24]([NH:29][C:11]([C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:23]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Cl)c2s1

Procedure:
176.2 mg (0.83 mmol) of 7-chloro-1-benzothiophene-2-carboxylic acid, 150 mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 4M HCl in dioxane and methanol and then concentrated. 231.9 mg (85.7% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 69.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([O:16][CH3:21])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)c1ncccc1C(=O)c1ccc(F)cc1

Procedure:
Treatment of 3-(4-fluorobenzoyl)pyridine-2-carboxylic acid with diazomethane, followed by silica gel chromotography (using hexanes-EtOAc (3:2) as the eluent), gives pure 3-(4-fluorobenzoyl)-2-carbomethoxypyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CCOC(C)=O>[O:22]([C:23]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccncc1)Oc1ccccc1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 4-(aminomethyl)pyridine (10.7 g, 98.5 mmol) in CH2Cl2 (245 mL) at 0°, was added Et3N (14.2 mL, 19.9 g, 197 mmol) followed by dropwise addition of phenylchloroformate (14.8 mL, 18.5 g, 118 mmol). After stirring for 1 h, the resulting mixture was diluted with EtOAc (1.5 L), the organic phase was washed twice with water and brine, dried over sodium sulfate and concentrated under vacuum. Chromatography (SiO2, gradient EtOAc to 10% MeOH/CHCl3) gave a yellow solid which was recrystallized from EtOAc:hexane (2:1), to yield the desired compound (9.55 g, 41.85 mmol, 42% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].C[Mg]Cl.[CH2:13]([Mg]Cl)[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]CCC.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:25]([OH:24])[C:26]#[C:27][CH2:28][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCCBr
Reactant: CCCC/C=C\CCC[Mg]Cl
Reactant: C1CCOC1
Agent: C[Mg]Cl
Product: CCCC/C=C\CCCCCCCCCC#CCO
Reaction time: 1 h

Procedure:
cis-13-Octadecen-2-yn-1-ol was synthesized in the following manner. Thus, 153 g (0.81 mole) of 8-bromo-1-octyne were added dropwise at 50° to 55° C. to 1 mole of methyl magnesium chloride dissolved in 300 ml of tetrahydrofuran and the mixture was agitated for 1 hour followed by the addition of 2 g of dilithium tetrachlorocuprate Li2CuCl4. Thereafter, a solution of 1 mole of cis-4-nonenyl magnesium chloride dissolved in 300 ml of tetrahydrofuran was added dropwise to the reaction mixture at 40° to 55° C. and the mixture was agitated for 4 hours at 48° C.
Reaction SMILES: C(OP(/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1.O>O1CCCC1.CCOCC>[CH3:19][C:20]1[S:21][C:22]([CH:25]=[CH:16][CH:15]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][N:24]=1
Reactant: Cc1ncc(C=O)s1
Reactant: C/C=C(/C(=O)OCC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cnc(C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 12.5 g of ethyl diethylphosphonocrotonate in 25 ml of tetrahydrofuran was added with stirring to a mixture of 100 ml of anhydrous tetrahydrofuran and 3 g of sodium hydride in 46% of an oil cooled to 0°C and the mixture was stirred for 30 minutes at 0°C. Then, a mixture of 6.4 g of 2-methyl-5-thiazolecarboxaldehyde in 25 ml of tetrahydrofuran was added to the mixture at 0°C and 250 ml of ice and 250 ml of water were added. The mixture was extracted with methylene chloride and the organic extracts were washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 13 g of raw product which was dissolved in ether and the ether solution was stirred in the presence of Florosil and then with activated carbon. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 11 g of ethyl 5-(2-methyl-5-thiazolyl)-2,4-pentadienoate in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:11].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1c(N)nc2ccccc21
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1c(NC(=O)OCC(Cl)(Cl)Cl)nc2ccccc21

Procedure:
To a solution of 1-methyl-1H-benzimidazol-2-amine (1.00 g, 6.79 mmol) and pyridine (0.646 ml, 8.15 mmol) in tetrahydrofuran (23 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.13 ml, 8.15 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 546 mg (24.9%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:14][NH:15][CH3:16].Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:14][N:15]([CH3:16])[CH2:12][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)s1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)Cc1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 13 (90 mg, 0.48 mmol) was added a solution of dimethylamine (2.9 M, 0.99 mL, 2.85 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.24 mL, 0.95 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (30 mg, 0.48 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 24 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.15) to afford the title compound 42 (57 mg, 55% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.85 (br s, 1H), 8.48 (m, 1H), 7.82 (m, 1H), 7.28 (m, 1H), 7.21 (d, J=3.7 Hz, 1H), 6.91 (d, J=3.5 Hz, 1H), 3.65 (s, 2H) 2.31 (s, 6H); LRMS (ESI) m/z calcd for C12H15N2S [M+H]+ 219. found 219; m/z calcd for C10H8NS [M−N(CH3)2]+ 174. found 174; HRMS (ESI) m/z calcd for C12H15N2S [M+H]+ 219.0956. found 219.0955; HPLC>99% (tR=8.90 min, 55 (A):45 (B): 0.009 (C); tR=6.28 min, 55 (A):45 (B): 0.018 (C)).