Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]=[C:7]1[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])C)C.[BH4-].[Na+].O[O:35][S:36]([O-:38])=O.[K+].[CH3:40]O>CO.C1COCC1.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2[N:8]=[C:7]([CH:26]([C:27]([F:29])([F:28])[F:30])[OH:31])[NH:6][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([S:36]([CH3:40])(=[O:38])=[O:35])=[CH:13][CH:12]=2)=[CH:20][CH:21]=1
Reactant: CCOC(C)n1c(C(=O)C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2[nH]c(C(O)C(F)(F)F)nc2-c2ccc(F)cc2)cc1

Procedure:
To a solution of 85 mg of 1-[1-(1-ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1H-imidazol-2-yl]-2,2,2-trifluoroethanone (Example 89, Step 1) (0.18 mmol) in 1 ml of methanol at 0° C. was added 10 mg of sodium borohydride (0.26 mmol). The solution turned immediately from yellow to colorless. The reaction was quenched with 1% solution of aqueous hydrochloric acid and diluted with methylene chloride then washed with brine. The organic extracts were dried (MgSO4), filtered and the solvent was removed under reduced pressure to provide 77.1 mg of a white film. All of this material was dissolved in 8 ml of methanol/THF (1.6:1). Oxone® (450 mg) was dissolved in 2 ml of water and the solution was added all at once. After stirring the reaction at 25° C. for 1.5 hours, the reaction was poured into water and extracted with methylene chloride. The organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a white foam which was purified by preparative thin layer chromatography (SiO2; 100% ethyl acetate) to give 50.5 mg of the desired sulfone: mp 126-130° C. Anal. Calc'd. for C18H14F4N2O3S: C, 51.49; H, 3.54; N 6.33. Found: C, 51.53; H, 3.26; N, 6.31.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:20])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:24][CH2:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].BrCCC(O)=O.C(N)CCC>O1CCCC1.C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCBr
Reactant: CCCCNC(=O)CCNS(=O)(=O)c1ccc(C)cc1
Agent: O=C(O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCNC(=O)CCN(CCC(=O)NCCCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve N-butyl-3-(toluene-4-sulfonylamino)-propionamide (10 mmol) prepared in Scheme VI, step B in tetrahydrofuran (50 mL) and treat with sodium hydride (10 mmol). Stir the reaction for 30 minutes and add 3-bromo-N-butyl-propionamide (10 mmol) [prepared from amidation between Br(CH2)2CO2H and butyl amine under conditions well known in the art as previously described generally]. Heat the reaction to reflux for 5 hours. After cooling dilute the reaction with methylene chloride (150 mL), rinse with water (100 mL), brine (100 mL), dry over sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N-butyl-3-[(2-butylcarbamoyl-ethyl)-(toluene-4-sulfonyl)-amino]-propionamide.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:35][NH2:36]>>[CH3:33][N:2]([CH3:1])[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(=O)N(C)C)cc1)N2
Reactant: NN
Solvent: O
Product: CN(C)C(=O)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
Ethyl 2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (500 mg, 1.12 mmol) and hydrazine monohydrate (8 mL) were added and the mixture was stirred under 40° C. for 3 h. Then the mixture was cooled to room temperature and filtered to give the title compound (90 mg, yield 19%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86 (s, 3H), 2.96 (s, 3H), 3.42 (s, 3H), 4.66-4.69 (d, J=10.4 Hz, 1H), 4.96-4.99 (d, J=10.4 Hz, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.16-7.19 (m, J=7.6 Hz, 1H), 7.29-7.45 (m, 6H), 7.56-7.60 (t, J=7.6 Hz 1H), 12.18 (s, 1H); LC-MS (ESI) m/z: 415 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]3([CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[C:19](=[O:22])([O-])[O-:20].[K+].[K+].C[N:26]([CH3:29])C=O>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]([CH2:16][NH:26][C:29]3[CH:7]=[CH:8][C:3]([C:19]([O:20][C:14]([CH3:17])([CH3:16])[CH3:13])=[O:22])=[CH:4][CH:5]=3)([OH:15])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1

Procedure:
A mixture of the compound (0.48 g) obtained in Step 3 of Example 1, the compound (0.44 g) obtained in Step 1, potassium carbonate (0.55 g) and anhydrous dimethylformamide (5 mL) was stirred at 95 to 105° C. for three hours under nitrogen atmosphere. Water (30 mL) was added to the resulting mixture and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue (1.1 g) obtained by removal of the solvent was purified by silica gel column chromatography (Chromatorex NH™)(eluent; hexane:ethyl acetate=1:1 to ethyl acetate) to obtain the titled compound (0.55 g) as crystals.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>O>[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=[N:29][OH:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1c(OCc2ccccc2)ccc2ccccc12
Yield: 97.8 %

Procedure:
To 460 ml of methanol and 150 ml of water were added 120 g (0.46 mole) of 2-benzyloxy-1-naphthaldehyde, 75 g (0.92 mole) of sodium acetate and 48 g (0.69 mole) of hydroxylamine hydrochloride, and the mixture was refluxed by heating for 2 hours. After the reaction, the reaction mixture was added to 1.5 liters of water. The precipitated crystals were collected by filtration to obtain 125 g (0.45 mole) of 2-benzyloxy-1-naphthaldoxime.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:6]=1.[CH:17](=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[C:11]1([C:9](=[O:10])[CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:17](=[O:20])[CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Reactant: CCC=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of (E)-1,3-diphenyl-propenone (1.042 g; 5.00 mmol), propionaldehyde (0.40 mL; 5.6 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (126 mg; 0.500 mmol) and triethyl-amine (0.42 mL; 3.0 mmol) in absolute ethanol (3.0 mL) was degassed then heated at 70° C. for 25 h. After an additional 1.5 h at 80° C., the organic volatiles were removed on a rotary evaporator. EtOAc (25 mL) was added and the solution washed with water (3×5 mL) and satd NaCl (2×5 mL); then dried (MgSO4), filtered through silica and washed through with EtOAc. Crude product was adsorbed onto silica (2.0 g) then purified by MPLC (40 g of silica using a 0→20% EtOAc in hexanes gradient). Pure product was obtained as a clear, pale tan liquid (760 mg; 57%). 1H NMR (CDCl3) δ 7.96 (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.38-7.26 (m, 5H), 4.43 (dd, J=3.4, 10.2 Hz, 1H), 4.05 (dd, J=10.4, 18.0 Hz, 1H), 3.14 (dd, J=3.8, 18.2 Hz, 1H), 2.65 (m, 1H), 2.53 (m, 1H), 1.02 (t(app), J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([S:31]CC4C=CC(OC)=CC=4)[CH2:28][N:27]3[CH3:41])=[O:25])[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O.CCOCC>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[N+:1]([C:4]1[CH:57]=[CH:56][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([SH:31])[CH2:28][N:27]3[CH3:41])=[O:25])[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)CNC(=NC(=O)OCc4ccc([N+](=O)[O-])cc4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 63.7 %

Procedure:
2.99 g of (2S,4S)-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylanino]pyrrolidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (1) above] were dissolved in a mixture of 21 ml of trifluoroacetic acid and 4.1 ml of anisole, and then 1.15 ml of trifluoromethanesulfonic acid were added dropwise, whilst stirring and ice-cooling, to the resulting solution. The reaction mixture was stirred for 20 minutes at room temperature, after which the mixture was poured into ether. The resulting precipitate was collected by filtration and the precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated sodium hydrogencarbonate, with water and with brine and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated by evaporation under reduced pressure to obtain 1.62 g of (2S,4S)-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-methylpyrrolidine, in the form of an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O.O>C(Cl)(Cl)Cl>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 140 °C
Yield: 3.9 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (2.0 g), diethyl ethoxymethylenepropanedioate (3.15 g) and N,N-dimethylformamide (16 ml) was stirred at 140° C. for an hour and a half. To the reaction mixture was added diethyl ethoxymethylenepropanedioate (1.57 g). The reaction mixture was stirred for an hour and cooled to ambient temperature. To the mixture was added water to five crystals, which were filtered off and dissolved in a mixture of chloroform and methanol. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, to which was added chloroform. The mixture was heated and insoluble materials were filtered off to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (0.12 g) melting at 310°-212° C. Further, the filtrate was concentrated under reduced pressure and allowed to stand at ambient temperature to give crystals (1.63 g), which were purified by a column chromatography on silica gel (60 g) (developing solvent: 3% methanol-chloroform solution). The crystals were dissolved in 10% methanol-chloroform solution. The solution was treated with activated charcoal and concentrated under reduced pressure. The residue was recrystallized from chloroform to give crystalline diethyl[{6-methanesulfonamido-4-quinazolinylamino}methylene]propanedioate (1.45 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25][CH2:26]2)=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(S(C)(=O)=O)CC2)cc1)C(=O)NCC#N
Reaction time: 2 h

Procedure:
To a solution of N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide from example 17, step 7 (102 mg, 0.23 mmol) in DMF (1 mL), was added methyl sulfonyl chloride (27 μL, 0.35 mmol) and cesium carbonate (91 mg, 0.28 mmol). The mixture was aged for 2 hours under nitrogen atmosphere and was diluted with dichloromethane. The resulting mixture was filtered over celite and concentrated under reduced pressure. The crude residue was chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-(4-{3-(4-phenyl-benzyl)imidazo[5,4-b]pyridin-2-ylmethoxy}benzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 55) and 36 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 450 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.CC#N.O>C(O)=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH2:3][CH2:2][F:1])[CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: O=c1[nH]c(CNCCF)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: O=CO
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(CCF)Cc2nc3c(c(=O)[nH]2)COCC3)CC1

Procedure:
Following the general procedure of Example 5, the title compound was prepared (0.09 g) from 2-((2-fluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (0.18 g, 0.79 mmol, 1 eq.) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (0.19 g, 0.71 mmol, 0.9 eq.). 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.18 (m, 2H), 7.26 (m, 2H), 4.71-4.80 (m, 1H), 4.60-4.67 (m, 1H), 4.59 (s, 2H), 4.48-4.53 (m, 1H), 4.46 (s, 1H), 4.37 (s, 2H), 3.89-3.96 (m, 2H), 3.83-3.90 (m, 1H), 3.77-3.84 (m, 1H), 3.66-3.78 (m, 3H), 3.46-3.61 (m, 1H), 3.16-3.28 (m, 1H), 2.49-2.73 (m, 2H), 1.91-2.25 (m, 4H). HRMS calculated for C24H29F2N4O4 475.2157. found (ESI, [M+H]+) 475.2178. MS (ESI) m/z 475.2 (M+H)+. Retention time: 4.08 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 m L/m in).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[CH3:33][N:34]=[C:35](OCC)[CH3:36].[OH-].[Na+]>O.C(#N)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([C:35](=[N:34][CH3:33])[CH3:36])[CH2:26]4)=[CH:22][CH:23]=3)[C:15]([OH:17])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:4])[NH2:5]
Reactant: N=C(N)c1ccc2sc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Reactant: CCOC(C)=NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN=C(C)N1CC[C@H](Oc2ccc(C(Cc3cc4cc(C(=N)N)ccc4s3)C(=O)O)cc2)C1
Yield: 33.2 %

Procedure:
2.0 g of 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride was dissolved in a solvent mixture of 10 ml of water and 10 ml of acetonitrile. With stirring, to the thus prepared solution was gradually added 20 g of ethyl (N-methyl)acetimidate hydrochloride which has been prepared in accordance with the procedure disclosed in The Journal of Organic Chemistry (vol.33, pp.1679-1681, 1968), while maintaining the pH level of the solution at 8.5 with 2N sodium hydroxide aqueous solution. After distilling off the solvent, the resulting residue was washed with dichloromethane and then subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent, thereby effecting desalting. Fractions of interest thus pooled were subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel. Thereafter, the thus eluted fractions of interest were pooled and then concentrated to dryness by passing through a C1 type of strongly basic ion exchange resin (Diaion SA-10, Nippon Rensui Co., Ltd.). In this way, 370 mg of the title compound was obtained in a solid form.
Reaction SMILES: CON(C)C([C:6]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH:7]=1)=O.Br[CH2:22][CH2:23]CC=C.[Mg].[NH4+].[Cl-].[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH:7]1[C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][C:6]=1[C:32](=[O:33])[CH2:31][CH2:30][CH2:34][CH:22]=[CH2:23]
Reactant: CON(C)C(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: C=CCCCBr
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: C=CCCCC(=O)c1ccc2c(ccc3ccccc32)c1
Reaction time: 2 h

Procedure:
Phenanthrene-2-carboxylic acid methoxy-methyl-amide (1 g) was dissolved in anhydrous THF (30 ml). A grignard prepared from 5-bromopentene (3 g) and magnesium in anhydrous THF (15 ml), as described in example 23, was added and the mixture stirred for 2 h. Saturated NH4Cl was added and the mixture extracted with petrol. The organic phase was dried and evaporated and purified by column chromatography (petrol/ethyl acetate) to give the title compound as a white powder. δC (CDCl3, 62.9 MHz): 23.4, 33.3, 37.9, 115.4, 123.2, 123.3, 125.1, 127.0, 127.4, 127.8, 127.9, 128.8, 129.4, 129.7, 131.5, 133.0, 133.3, 134.8, 138.2 and 200.1
Reaction SMILES: [C:1]([C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:8][CH2:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][CH2:4]1)#[N:2].O1CCCC1.[OH-].[K+]>CO.O>[C:1]([C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:8][CH2:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CC=C(C(=O)O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0.07 g, 0.18 mmol) in methanol (0.5 mL, containing just enough tetrahydrofuran to solubilize the ester) under an argon atmosphere was added a solution of potassium hydroxide (0.03 g, 0.55 mmol) in water (0.4 mL). The resulting mixture was stirred at room temperature for 4 h, then poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 3N hydrochloric acid and extracted twice with ethyl acetate. The organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a viscous oil, which solidified upon standing. The solid was recrystallized from hexanes/methylene chloride (0.05 g, 82%): m.p. 161°-163° C.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[CH2:1]([CH:7]1[CH:11]([CH2:16][N+:13]([O-:15])=[O:14])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+](=O)[O-]
Reactant: CCCCCCC1=CCCC1=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCC1C(=O)CCC1C[N+](=O)[O-]

Procedure:
In a 2-L flask fitted with a reflux condenser, is placed 332 g of 2-n-hexyl-2-cyclopentenone, 183 g of nitromethane, 30 ml of 40% methanolic solution of benzyltrimethylammonium hydroxide (Triton B) and 200 ml of dry dioxane. The reaction mixture is refluxed for 23 hours. The solvent is distilled off under a reduced pressure and the residue is dissolved in 1 L of ether. The ether solution is washed successively with dilute hydrochloric acid, water and sodium bicarbonate solution and dried over anhydrous sodium sulphate. The solvent is removed at atmospheric pressure and the residue is distilled through a short Vigreux column. After a lower boiling fraction (35 g, 65° C/0.2 mm) consisting of 2-n-hexyl-2-cyclopentenone, the product is collected at 135° C/0.3 mm, yield 365 g (80%), nD20 1.4733.