Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:8][C:7]=1[CH2:22]O>C(OCC)(=O)C>[Cl:3][CH2:22][C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CO)c2)c1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Reaction time: 1 h

Procedure:
Add thionyl chloride (0.59 mL, 8.07 mmol) to a solution of 5-(4-fluoro-3-hydroxymethyl-phenylethynyl)-nicotinonitrile (1.85 g, 7.33 mmol), (prepared as described in EXAMPLE 142). After 3 h add an additional 0.2 mL of thionyl chloride and stir for another 1 h. Dilute the reaction mixture with ethyl acetate and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify the crude material by silica gel chromatography, eluting with a gradient from 85:15 to 75:25 hexanes:ethyl acetate, then elute with 50:50 hexanes:ethyl acetate to give the title compound. Further purify by additional silica gel chromatography, eluting with 90:10 (70:30 hexanes:dichloromethane):ethyl acetate. Combine clean fractions from both chromatographies and concentrate to give the title compound as a crystalline solid (1.5 g, 75%).
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[F:41][C:42]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=1[NH2:44].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[F:41][C:42]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=1[NH:44][C:19](=[O:21])[CH2:18][N:16]1[N:15]=[N:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:17]1
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCc1nnn(CC(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(CC(=O)Nc2ccc(F)cc2F)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4-difluoroaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 103°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].[Cl-].[NH4+].[OH-].[Li+]>CN(C)C(=O)C.O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(NS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (412 mg) synthesized in Example A110(5) in N,N-dimethylacetamide were added triethylamine (160 μL) and methanesulfonyl chloride (89.0 μL), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL), ethanol (5 mL) and water (1 mL) was added 4N lithium hydroxide aqueous solution (500 μL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (379 mg, 91%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:32]([O:36][NH2:37])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=1)[C:13]([NH:37][O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CSc1ccc(Oc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)ONC(=O)[C@H](CSc1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The above-prepared (R)-2-(benzyloxycarbonylamino)-3-(4-phenoxyphenylthio)-propionic acid was dissolved in methylene chloride (175 ml), cooled to 0° C., and treated with O-(tert-butyl)hydroxylamine hydrochloride (7.7 g), 4-methylmorpholine (9.4 ml), 1-hydroxybenzotriazole (2.8 g), and N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (7.9 g). The mixture was allowed to warm to room temperature, stirred for 1.5 hours, then partitioned between methylene chloride and water. Solvent was removed from the organic phase under reduced pressure, and the residue purified by flash chromatography on silica gel, eluting with 0 to 50% ethyl acetate/hexane, to provide (R)-2 -(benzyloxycarbonylamino)-N-tert-butoxy-3-(4-phenoxyphenylthio)-propionamide (7.4 g) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A solution of 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (8.1 g, 22.8 mmol), (S)-(+)-2-methylpyrrolidine (2.33 g, 27.36 mmol), K2CO3 (6.93 g, 50.16 mmol) in acetonitrile (76 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-methylpyrrolidine (834 mg, 9.79 mmol), and the temperature of the reaction mixture was maintained at 80° C. for 20 h. The heating was removed and the solution was concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.43 g (40% yield) of the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[S:7][C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[S:7][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:9]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Yield: 98.1 %

Procedure:
To a stirred solution of 0.15 g (0.40 mmol) of the above ester in a mixture of 2 mL of THF and 1 mL of H2O was added 0.60 mL (0.60 mmol) of 1 N NaOH at room temperature. The resulting mixture was refluxed for 3 h. The solvent was evaporated in vacuo. The residue was dissolved in 5 mL of H2O and acidified with 0.11 mL of 1N HCl to give 0.14 g (100%) of 1 as a pale yellow solid: mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 9.75 (brs, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.62 (s, 1H), 7.462 (d, J=8.6 Hz, 2H), 7.46 (m, 5H), 3.71 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.6, 176.5, 150.6, 140.9, 138.8, 137.2, 136.1, 132.4, 130.6, 129.7, 129.3, 129.2, 129.1, 128.9, 34.0; IR (KBr) cm−1 3058, 2921, 1715, 1628; LREIMS C19H13ClO3S requires 356.03. Found: 355 ([M+], 100%), 310 (25%), 244 (25%), 139 (42%).
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[F:6][P-:7]([F:12])([F:11])([F:10])([F:9])[F:8].[H+]>CCOCC>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[F:6][P-:7]([F:12])([F:11])([F:10])([F:9])[F:8]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 0 °C

Procedure:
A mixture of one of these anthranils (1 part) and a tert-alkanol (1.1 to 1.2 parts) is warmed to effect solution, then is cooled in an ice-water bath while 70% perchloric acid or 60% hexafluorophosphoric acid (2 parts) is added at a rate which maintained the internal reaction temperature ≤35° C. After addition, the reaction mixture is stirred with ice-water cooling while the precipitate formed over about 30 minutes. This is slurried in ether and the salts are collected by filtration, washed with dry ether, and dried under vacuum to give the N-tert-alkyl anthranilium perchlorate or hexafluorophosphate salt as pale yellow solids in high yields.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[O:18]1CCC[CH2:19]1>>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:19](=[O:18])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCNc1c(N)cccc1N
Product: CCOC(=O)CCCn1c(=O)[nH]c2cccc(N)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of ethyl 4-[(2,6-diaminophenyl)amino]butanoate (35.1 g, 0.148 mol), N,N′-carbonyldiimidazole (74.5 g, 0.444 mol) in tetrahydrofuran (600 mL) was stirred at room temperature for 16 hr. The mixture was concentrated, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (26.5 g, 0.101 mol, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:15][C:16]1C=CC(C#C)=CN=1>>[C:15]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1)#[CH:16]
Reactant: C#Cc1ccc(C)nc1
Reactant: Brc1ccc(CN2CCOCC2)nc1
Product: C#Cc1ccc(CN2CCOCC2)nc1

Procedure:
4-(5-Ethynyl-pyridin-2-ylmethyl)-morpholine was prepared from 4-(5-bromo-pyridine-2-ylmethyl)-morpholine (U.S. Pat. No. 6,358,945) in the same manner as 2-methyl-5-ethynyl pyridine (Example 7).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 mL) was added to a suspension of activated manganese dioxide (27 g) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde, as an oil. NMR and IR were consistent with the structure.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([N:25]([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([O:7][C:8](=[O:9])[NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][C:16]([N:25]([CH3:27])[CH3:26])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The chloroformic acid phenyl ester (1.32 ml, 10.5 mmole) dissolved in abs. DCM (25 ml) was slowly added dropwise while cooling with iced water to a solution of (4-aminomethyl-1-phenylcyclohexyl)-dimethylamine (2.32 g, 10 mmole) in abs. DCM (25 ml) and pyridine (888 μl, 11 mmole). The reaction mixture was then stirred for 20 hours at RT. The reaction mixture was worked up by extraction with water (3×10 ml), with 1M HCL (3×10 ml) and with 1M NaOH (2×10 ml). The organic phase was dried with Na2SO4 and then concentrated by evaporation. The residue was the diastereoisomer mixture of (4-dimethyl-amino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester. This was obtained as a colourless solid in a yield of 3.18 g (m.p. 108°-124° C., 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:15])[N:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][C:8]=1C(O)=O)[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(=O)=O>S(=O)(=O)(O)O>[CH:12]([N:6]1[CH2:7][C:8]([N+:16]([O-:18])=[O:17])=[C:4]([O:3][CH2:1][CH3:2])[C:5]1=[O:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CCOC1=C(C(=O)O)CN(C(C)C)C1=O
Agent: O=C=O
Agent: O=S(=O)(O)O
Product: CCOC1=C([N+](=O)[O-])CN(C(C)C)C1=O
Temperature: -5 °C
Reaction time: 3 h

Procedure:
3-Ethoxy-1-isopropyl-2-oxo-3-pyrroline-4-carboxylic acid (5b, 8 g, 0.0376 mol) in powdered form was added in small portions through a seive to a stirred mixture of 70 mL of concentrated sulfuric acid and 4.7 mL of white fuming nitric acid (90%) that had been cooled to -5° C. prior to the start of the addition of 5b. The rate of addition of 5b was controlled so as to keep the temperature of the reaction mixture from rising above -3° C. and to minimize accumulation of undissolved lumps of starting material in the mixture. Stirring was continued for 3 h at -3° C. Effervescence caused by carbon dioxide evolution began after the mixture had been stirred for a few minutes and virtually ceased after an hour of two. When the mixture was poured slowly into a stirred suspension of 1 L of crushed ice, the product separated as a white crystalline precipitate. It was collected by filtration as soon as the ice was melted and washed on the filter with a small amount of cold water. The yield was 4.9 g (61%), mp 47°-47° C. Recrystallization from acetone or benzene and petroleum ether (bp 30°-60° C.) raised the melting point to 49°-50° C.: 1H NMR (CDCl3) δ4.90 (q, 2H, OCH2CH3, J=7 Hz), 4.40 (septet, 1H, NCH(CH3)2, J=7 Hz), 4.15 (s, 2H, CH 2 of pyrroline), 1.55-1.20 (t+d, 9H, overlap of --OCH2CHc and NCH(CH3)2, J=7 Hz); IR (thin film) 3.34, 3.39, 3.47, 5.87, 6.08, 6.69, 6.92, 7.17, 7.3, 7.30, 7.38, 7.67, 7.93, 8.10, 8.40, 8.55, 8.75, 8.87, 9.05 μm; UV (95% EtOH) 293 nm (ε9800).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=O.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[CH:19][C:17](=[O:18])[C:16]([OH:21])=[O:20]
Reactant: CC(=O)C(=O)[O-]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(C=CC(=O)C(=O)O)c1C
Temperature: 0 °C
Yield: 100 %

Procedure:
A suspension of 3.7 g (17.6 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde and 5.0 g (53.2 mmol) of sodium pyruvate in 20 ml of methanol is treated with 0.1 g (1.8 mmol) of potassium hydroxide and the mixture is subsequently heated at reflux for 5 hours, whereby a yellow solution is obtained. The reaction mixture is poured on to ice-water and the resulting 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid is precipitated by the addition of sulphuric acid while stirring. The suspension is stirred for 1 hour, filtered, the filter residue is washed with water and dried. In this manner there are obtained 4.9 g of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid in the form of a yellow powder of melting point 126°-127° C.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[F:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH:4][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1ccc(N)c(F)c1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1F)C(=O)OCC
Temperature: 80 °C
Yield: 92.5 %

Procedure:
To a solution of 2-fluoro-3,4-dimethoxyaniline (39 g, 228 mmol) in Ethanol (200 mL) was added diethyl 2-(ethoxymethylene)malonate (45.7 mL, 228 mmol), and the resulting mixture was heated at 80° C. for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to remove ethanol and then washed with hexane to afford diethyl 2-(((2-fluoro-3,4-dimethoxyphenyl)amino)methylene)malonate (72 g, 211 mmol, 93% yield) as a brown solid. LCMS (M+H)+: 342.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=S)[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2].C(N(C(C)C)CC)(C)C.CI.[NH2:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([NH:37][CH2:38][CH2:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[N:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2]
Reactant: NCCC1CCOCC1
Reactant: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(=S)NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(NCCC4CCOCC4)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-quinolin-2-yl]-acetamide (example 6a, 50 mg, 0.11 mmol) in acetonitrile (1.5 ml) was reacted with diisopropylethyl amine (0.200 ml, 1.15 mmol) and methyl iodide (0.15 ml, 2.3 mmol) at rt for 30 min. The mixture was concentrated to dryness and the residue suspended in acetonitrile (1.5 ml). Diisopropylethyl amine (0.20 ml, 1.15 mmol) and 4-(2-aminoethyl)tetrahydropyran (0.075 ml, 0.58 mmol) were successively added at rt, and the mixture was stirred at rt overnight. The precipitate was collected by suction filtration, an washed with acetronitrile. It was then absorbed on SiO2 and purified on a silica gel column with a 0–10% methanol/ethyl acetate gradient to afford the product N-(4-ethoxy-6-{4-oxo-2[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-quinolin-2-yl)-acetamide as a pale yellow solid (22 mg, 50%). LC-MS m/e 469 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]=[N+]=[N-])[CH2:10]2)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([NH2:14])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(N=[N+]=[N-])C2
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1C2CCC1CC(N)C2
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of 3-azido-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.42 g, 6.28 mmol) in methanol (62 mL) was added Pd (10% weight on carbon, 100 mg). The mixture was degassed and charged with hydrogen (g) 3×, and stirred for 12 hrs. The mixture was filtered through celite and concentrated. The crude residue was purified by flash chromatography (gradient elution: 0→20% MeOH/dichloromethane) to provide 855 mg of a clear oil (68%, 3 steps). 1H NMR (300 MHz, CDCl3) □ ppm 1.26 (t, J=7.1 Hz, 3H), 1.66 (m, 4H), 1.83 (m, 2H), 1.95 (m, 2H), 3.16 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.27 (m, 2H); MS (ESI+Q1MS) m/z 199 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:9][CH:8]=1)[C:4](O)=[O:5].S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:20])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:9][CH:8]=1)[C:4]([Cl:23])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)(F)C(F)F)cc1
Solvent: c1ccccc1
Product: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)C(F)F)cc1
Yield: 105.6 %

Procedure:
A stirred mixture of 20.00 g (0.0680 mol) of 3-methyl-2-[p-(1,1,2,2-tetrafluoroethoxy)phenyl]butyric acid, 20.00 ml (33.2 g, 0.280 mol) of thionyl chloride (Baker), and 75 ml of dried benzene is refluxed for 4 hours. The reaction mixture is then evaporated and the resulting residue is diluted with 50 ml of benzene and again evaporated to give 22.46 g (106%) of a clear dark brown liquid. This product is used as is in the subsequent reactions. The liquid is examined by infrared analysis and determined to be the above-named product.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4](=[O:6])[CH3:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1.O>C(Cl)Cl>[C:15]([O:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4](=[O:6])[CH3:5])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(O)CCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(CCc1ccccc1)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 850 mg of 4-hydroxy-6-phenylhexan-2-one (T. Mukaiyama et al., Chemistry Letters 1976, 95) in 10 ml of methylene chloride were added 1 ml of acetic anhydride and 0.8 ml of pyridine under ice-cooling at 0° C., and then stirring was continued for further 1 hr at room temperature. The reaction mixture was poured into water, the methylene chloride layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to afford 1.10 g of the desired compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCC(CCCO)CC1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(CCCCl)CC1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a stirred mixture of 36 parts of ethyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate and 261 parts of benzene were added dropwise 21.5 parts of thionyl chloride at 5°-10° C. Upon complete addition, stirring was continued overnight at this temperature. The reaction mixture was evaporated and the residue was taken up in methylbenzene. The solvent was evaporated (this was repeated twice), yielding 33 parts (83.8%) of ethyl 4-(3-chloropropyl)-1-piperidinecarboxylate as a residue (int. 58).