Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>>[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccccc1/C=C/c1ccncc1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To 15.1 g of 2-nitrobenzaldehvde was added 9.3 g of 4-picoline followed by addition of 5 ml of acetic anhydride and the mixture was refluxed for 12 hours. This reaction mixture was poured in ice-water, made basic with 2N--NaOH, and extracted with chloroform. The extract was dehydrated over anhydrous magnesium sulfate and the solvent was evaporated off to provide 22.40 g of (E)-2-[2-(4-pyridyl)ethenyl]-1-nitrobenzene. This product was treated as in Reference Example 2 (2) to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)ccn1
Yield: 51.1 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (108 mg, 51%). MS (ISP) 423.3 [(M+H)+]; mp 232° C.
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[CH3:49][OH:50]>>[CH3:49][O:50][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CO
Product: COc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using methanol in place of morpholine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.40 (s, 1H), 9.55 (m, 1H), 8.98-8.96 (m, 1H), 8.39-8.36 (m, 2H), 7.87-7.47 (m, 10H), 7.16-7.14 (m, 1H), 4.62-4.61 (m, 2H), 3.88 (s, 1H), 3.86 (s, 3H), 2.62-2.58 (m, 2H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32](=[N:34]O)[NH2:33]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[N:34]=[C:20]([CH:8]2[CH2:9][CH:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=3)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]2)[O:22][N:33]=1
Reactant: NC(=NO)c1c(F)cccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 23 mg (26% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[CH:8]=1)[CH3:2].[Cl-].[NH4+]>C(O)C.C1COCC1.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([Cl:16])[CH:8]=[C:7]2[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 6, 3.0 g, 11.0 mmol) was dissolved in ethanol (100 mL) and THF (50 mL). Iron powder (3.7 g, 66.0 mmol) and saturated ammonium chloride solution (50 mL) were added and the mixture was heated under reflux for 2 h. The mixture was cooled, filtered through celite and washed several times with ethyl acetate. The organic layers were combined, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound. δH (CD3OD): 1.42 (3H, t), 4.44 (2H, q), 7.15 (1H, s), 7.70 (1H, s), 8.59 (1H, s); m/z (ES+)=225 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Reactant: NCc1ccccc1
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.BrC1C=CC=[C:30]([F:34])C=1>>[F:25][C:2]([F:26])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:30]([F:34])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=397.1 (M+H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:14][CH:15]1[NH:19][C:18](=[O:20])[CH2:17][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCC.O1CCCC1>[C:21]([N:19]1[CH:15]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17][C:18]1=[O:20])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16.5 cm3 of a 15% solution of butyllithium in hexane is added at -60° C. to 5.3 g of 5-n-octyloxy pyrrolidin-2-one in solution in 200 cm3 of tetrahydrofuran. After agitation for 20 minutes at -60° C., then, while maintaining these conditions, a solution of 3.5 g of benzoyl chloride in 50 cm3 of tetrahydrofuran is added. Agitation is continued while allowing to return to ambient temperature. After concentration and chromatography on silica (eluent: toluene-ethyl acetate 8-2), 4.2 g of the product sought is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:1].[NH2:8][C:6]1[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(Cl)ccc1C=NO
Reaction time: 0.5 h

Procedure:
15.5 g (57 mmol) of tert-butyl {6-chloro-3-[(hydroxyimino)methyl]pyridin-2-yl}carbamate (Example 3A) were dissolved in 285 ml of 4 N hydrogen chloride in dioxane and stirred for a further 30 min. The reaction mixture was concentrated by half and the same amount of diethyl ether was added. The reaction mixture was stirred for a further 20 min and the product was filtered off and washed with diethyl ether. 11 g (94% of theory) of the product were obtained in solid form.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:29]([OH:34])[CH:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O1CCOCC1>CO.[Pd]>[OH:34][CH:29]([CH:30]([OH:33])[CH2:31][OH:32])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC(O)C(O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: OCC(O)C(O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.3 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2,3,4-trihydroxybutan-1-yl)oxy]quinazoline (800 mg) in methanol (6 ml)--dioxane (6 ml) is added 10% palladium/carbon (160 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 17 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallized from acetone, and the resulting crystalline substance is recrystallized from ethanol-diethyl ether to give 4-[(2RS,3SR)-(2,3,4-trihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (316 mg) as crystals.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[C:29]([O:33][C:34]([N:36]1[C:40]([CH:41]2[CH2:43][CH2:42]2)=[CH:39][C:38]([NH2:44])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl>[CH:41]1([C:40]2[N:36]([C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[N:37]=[C:38]([NH:44][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:39]=2)[CH2:42][CH2:43]1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(NC(=O)C(c2ccccc2)c2ccccc2)cc1C1CC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a solution of 45.6 mg (0.215 mmol) of diphenylacetic acid in 3 ml of dichloromethane at 0° C. 41.2 mg (0.215 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added. After 1 hour at the same temperature under stirring 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained at room temperature for 16 hours, then was diluted with dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was dried over anhydrous sodium sulfate evaporated to dryness, to give, after column chromatography (hexane-ethylacetate) 60 mg (80% yield) of N-(5-cyclopropyl-1-terbutoxycarbonyl-pyrazol-3-yl)-2,2-diphenyl acetamide. This intermediate was submitted to hydrolysis with 15 ml of trifluoroacetic acid 10% v/v in dichloromethane for an hour. The solvent was then evaporated under vacuum. the residue redissolved with dichloromethane and washed with a saturated solution sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 42 mg (92% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=O.Cl.[NH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([NH:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CC(C)(O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CC(C)(C)O)cn4n3)ccc2C)n(C)n1
Yield: 65.4 %

Procedure:
In the same manner as in Example 278 and using 3-hydroxy-3-methylbutanoic acid (74 mg, 0.63 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (240 mg, 0.63 mmol), N,N-diisopropylethylamine (190 mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (150 mg, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[S:7])=[CH:4][CH:3]=1.C(Cl)CCl.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>[Ti](Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:22]=[C:21]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:20]([OH:29])=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:24]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=S)Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCCCCC
Product: Cc1ccc(C(=S)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 54.4 g. (0.29 mole) of 4-methylthiobenzoyl chloride in 200 ml. of dichloroethylene is added gradually to 55 g. (0.29 mole) of titanium tetrachloride. After cooling this mixture, a solution of 60 g. of 2,6-di(t-butyl)phenol in 200 ml. of dichloroethylene is added. The resulting mixture is stirred for several hours, then hydrolyzed with 10 percent hydrochloric acid. The organic layer is separated, washed with water, dried and evaporated to provide a yellow oil. This product is mixed with hexane to provide a white solid which is recrystallized from hexane to provide 4-(4-methylthiobenzoyl)-2,6-di(t-butyl)phenol, m.p. 135°-136 C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.C1(C)C=CC=CC=1>O>[C:1]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: COCCOCCO
Solvent: O
Solvent: Cc1ccccc1
Product: C#CC(=O)OCCOCCOC

Procedure:
12.3 ml (0.2 mol) of propiolic acid were boiled at reflux for 20 hours together with 23.6 ml (0.2 mol) of diethylene glycol monomethyl ether, 1.5 g (8 mmol) of P-toluenesulphonic acid monohydrate and 80 ml of toluene, with the resulting reaction water being distilled off azeotropically and being collected in a water separator. After completion of the water separation the reaction mixture was washed in succession with saturated sodium bicarbonate solution and with water. The toluene phase was dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 2-(2-methoxyethoxy)ethyl propiolate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]2[C:4](=[O:7])[C:3](=[O:8])[C:2]=2[NH2:1])[CH:15]=1)[CH3:12]
Reactant: CN(C)Cc1ccnc(OCCCN)c1
Reactant: COc1c(N)c(=O)c1=O
Solvent: c1ccncc1
Product: CN(C)Cc1ccnc(OCCCNc2c(N)c(=O)c2=O)c1

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione is mixed with 3-[4-(dimethylaminomethyl)pyrid-2-yloxy]prop-1-yl-amine in anhydrous pyridine and is heated at reflux temperature to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:18][CH2:19][CH3:20])=[O:10].Br[C:22]1[S:23][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:25]([C:27]2[CH:32]=[N:31][C:30]([Cl:33])=[CH:29][N:28]=2)[N:26]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:25]2[N:26]=[C:22]([N:15]3[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([C:3]4[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=4[Cl:1])=[O:10])[C@@H:13]([O:18][CH2:19][CH3:20])[CH2:14]3)[S:23][C:24]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:28][CH:29]=1
Reactant: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To the stirred the solution of 3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 26, 650 mg, 2.03 mmol) and ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 636 mg, 1.828 mmol) in N-methylpyrrolidine was added N,N-diisopropyl ethylamine and stirred at stirred at 60° C. for 3 h. The reaction mixture was cooled to room temperature and poured on to ice water. The precipitate was collected by filtration and dried to afford 950 mg (79%) of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [O:1]=[C:2](C)[C:3]([NH:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])=O.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:9]([C@@H:7]1[NH:8][C:2](=[O:1])[C:3](=[CH2:18])[NH:5][C:6]1=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)C(=O)NC(=O)[C@@H](N)Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1NC(=O)[C@H](Cc2ccccc2)NC1=O
Yield: 1789.5 %

Procedure:
Using a Dean-Stark trap whose trap part was filled with molecular sieves 3A, a solution of N-2-oxo-propanoyl-L-phenylalanine amide from Example 1a (100 mg, 0.427 mmol) in toluene (20 mL) was refluxed in the presence of p-TsOH.H2O (4.37 mg, 0.023 mmol, 0.05 eq) for 18 h. After removal of the solvent, the residue was triturated in ether to obtain 89 mg (96%) of the title compound as a white solid: mp 175-177° C. (decomp); 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.41 (s, 1H), 7.24-7.11 (m, 5H), 4.90 (s, 1H), 4.50 (s, 1H), 4.40-4.37 (m, 1H), 3.15 (dd, J=3.8, 13.5 Hz, 1H), 2.91 (dd, J=5.0, 13.5 Hz, 1H); HRMS (EI): m/z 216.0891(M+) (calcd for C12H12N2O2: 216.0899). Enantiomeric excess was determined to be >99% using chiral HPLC with a CHIRALCEL OD column.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13](O)=O>>[CH3:1][N:2]1[CH:13]=[N+:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:4]=[C:3]1[S-:12]
Reactant: CNC(=S)NNc1ccccc1
Reactant: O=CO
Product: Cn1c[n+](-c2ccccc2)nc1[S-]

Procedure:
To 150 ml of formic acid was added 18.1 g of 4-methyl-1-phenylthiosemicarbazide obtained in the above process and the mixture was heat-refluxed for 20 hours. After cooling the reaction mixture and crystals thus formed were collected by filtration and recrystallized from methanol to provide mesoionic 4-methyl-1-phenyl1,2,4-triazolium-3-thiolate as light yellow crystals.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([N:18]=[C:19]=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:19]([NH:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)=[O:20]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N=C2CCCN2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After dissolving 5.4 g. (0.055 mole) of 2-imino-1-methylpyrrolidine in dry benzene, 9.85 g. (0.055 mole) of 3,4-dimethoxyphenylisocyanate (prepared according to the method of J. G. Lombardino and C. T. Gerber, J. Med. Chem., 7, Jan. 1964, p. 101), dissolved in dry benzene, is added dropwise to the solution. The reaction mixture is stirred at room temperature overnight (about 16 hrs.). The solvent is evaporated in vacuo and the residue, which solidifies on cooling, is triturated with anhydrous methanol. Repeated recrystallization from methanol yields the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(3,4-dimethoxyphenyl)urea, m.p. = 118°-120° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br:9][C:10]1[CH:11]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([O:22][CH3:23])=[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([N:19]1[CH2:18][CH2:17][N:16]([C:14]2[CH:15]=[C:10]([Br:9])[CH:11]=[C:12]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=2[O:22][CH3:23])[CH2:21][CH2:20]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(N2CCN(C(=O)COC(C)=O)CC2)cc(Br)cc1C(C)(C)C
Reaction time: 1 h

Procedure:
Acetoxyacetyl chloride (0.14 ml) was added to a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (360 mg) and triethylamine (0.31 ml) in CH2Cl2 (5 ml) while cooling on ice and the mixture was brought to room temperature and stirred for 1 hour. After quenching the reaction with brine, extraction was performed with ethyl acetate to yield a crude product of 2-{4-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazino}-2-oxoethyl acetate as a red oil. This crude product was dissolved in methanol (2.5 ml) and potassium carbonate (167 mg) was added. After 15 minutes, brine was added, extraction was performed with ethyl acetate, the extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (285 mg) as light orange crystals (67%).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[NH:9][CH2:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cn2nccc2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 65D (3.1 g) in dichloromethane (10 mL) was added TFA (10 mL) and the mixture was stirred overnight. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (300 mL) and washed with 2N aqueous NaOH, water and brine. The combined organic layers were concentrated, and the residue was dissolved in dichloroethane (30 mL) and MnO2 (2.5 g) was added. The mixture was stirred overnight. Filtration and evaporation of the solvent provided the title compound.