Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[BrH:13].N([O-])=O.[Na+]>O.[Cu]Br>[Br:13][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1
Reactant: Br
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cc(-c2ccccc2)[nH]n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
20 g of 3-amino-5-phenylpyrazole were suspended in 200 ml of a 24% aqueous hydrogen bromide solution and a solution of 9.5 g of sodium nitrite in 20 ml of water was added dropwise at 0° C. in the course of 10 min. The mixture was stirred at 0° C. for 10 min. Then the obtained suspension was added in portions to a suspension of 19.8 g of copper(I) bromide in 100 ml of a 24% aqueous hydrogen bromide solution. Subsequently, the mixture was stirred at room temperature for 2 h and then extracted three times with 300 ml each of EA. The combined organic phases were washed twice with 100 ml each of water and once with 100 ml of a saturated aqueous sodium carbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP (1:5) yielded 5.7 g of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[NH2:21][OH:22]>O1CCOCC1.C1COCC1>[OH:22][NH:21][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)[N:17]=1)=[NH:19]
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: NO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
With heating, 0.4 g (1.4 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide were dissolved in 40 ml of dioxane-THF 1:3, 0.4 ml of hydroxylamine (50% strength aqueous solution, corresponds to 6.8 mmol) was added and the mixture was stirred at 60° C. for 1 h and then concentrated by evaporation. The crude product obtained in this manner was not purified any further.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccoc1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccoc1
Temperature: 4 °C
Yield: 64.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-furancarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g). The product produced by precipitation in water (13 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (80 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-furancarboxamide (10.7 g) is produced, m.p. 102° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NN1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
(S)-1-(tert-Butoxycarbonylamino)-3-hydroxypyrrolidine (40 g, 0.21 mol) was dissolved in anhydrous methylene chloride (400 mL), in the presence of N,N-diisopropyl-ethylamine (73 mL, 0.42 mol, 2 equiv.) and cooled using an ice bath. This solution was treated with methanesulfonyl chloride (18 mL, 0.23 mol, 1.1 equiv.) over a 30 min. period and was then allowed to stir at room temperature for 4 h. The solution was concentrated and the residue dissolved in ethyl acetate (250 mL). The resulting organic solution washed with 5% NaHCO3 and then with brine. The organic extract was dried over magnesium sulfate, filtered and concentrated to give (S)-1-(tert-butoxycarbonyl-amino)-3-methanesulfonyloxypyrrolidine as a dark oil (39 g) which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere, 45.0 g (0.209 mole) of 2-amino-3'-fluorobenzophenone was added in four portions at 15 min intervals to a stirred melt (120°-125° C.) of 38.2 g (0.241 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 120°-125° C. for one hr. and then at 145°-150° C. for 45 min. The mixture was cooled to 130° C. and 100 ml of toluene was added. The cooled mixture (room temperature) was diluted with 100 ml of ethyl acetate and extracted with 100 ml of 10% potassium hydroxide. The organic layer was extracted with three 100 ml portions of 3N hydrochloric acid, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 35.5 g (50%) solid. The solid was dissolved in 200 ml of methylene chloride and the solution stirred with 50 g of fluorisil for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo. A 5 g portion of the residue was recrystallized from ethyl acetate-isopropyl ether to give 4.1 g of yellow-orange solid, m.p. 98°-101° C.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:26])[C:10](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3)nc2n(CCC)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Yield: 84.2 %

Procedure:
Compound 1 obtained in Example 1 (2.00 g, 5.90 mmol) was dissolved in 65 ml of N,N-dimethylformamide. To the solution were added 2.04 g (14.8 mmol) of potassium carbonate and then 0.74 ml (11.8 mmol) of methyl iodide, and the mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble substances were removed by filtration, and 500 ml of water was added to the filtrate. The mixture was extracted three times with chloroform, and the combined organic layers were washed twice with water and twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20% ethyl acetate/hexane), followed by recrystallization from ethanol/water to give 1.75 g (yield: 84%) of Compound 2 as white needles.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C(=O)CCC1=O.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(OCC)(=O)C>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C:30]([N:50]1[CH2:51][CH2:52][N:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[CH2:48][CH2:49]1)=[O:32]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Under cooling with ice, an ethyl acetate solution (40 ml) of N,N'-dicyclohexylcarbodiimide (10.3 g) was added dropwise to an ethyl acetate solution (150 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (12.5 g) and N-hydroxy succinimide (5.76 g), and the mixture was stirred at room temperature for 3 hours. While cooling again with ice, 1-(2-pyridyl)piperazine (8.16 g) was added, and the mixture was stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was washed first with an aqueous sodium carbonate solution and then with a saturated sodium chloride solution, dried over sodium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. The reaction mixture was purified by silica gel column chromatography (developing solvent:methylene chloride:methanol=10:1) to yield 16.1 g of tert-butyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl carbonyl]butylcarbamate (yield: 85.6%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[N:22][N:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:21][N:22]=1)(=[O:26])=[O:27])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nnc(-c2ccc(Cl)cc2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.4 g, 6.4 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was added 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride (1.5 g, 5.1 mmol) at 0° C. Then triethylamine (2.7 mL) was slowly added. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated, followed by column chromatography to give the title compound (1.1 g, 2.7 mmol, 53%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.08 (d, 2H), 7.66 (d, 2H), 4.03 (q, 2H), 3.26 (s, 2H), 3.15 (t, 2H), 2.64 (t, 2H), 1.14 (t, 3H).
Reaction SMILES: [Na].Cl.[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[NH:10][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:9]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2ccc(Cl)cc2)=N1

Procedure:
To a stirred solution of 56.4 g. of sodium metal in one liter of absolute ethanol there is added 156 g. of p-chlorobenzamidine hydrochloride followed by the dropwise addition of 144 g. of diethyl malonate over a thirty minutes period. The reaction mixture is heated under reflux for five hours. The solution is filtered and the filter cake is dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid precipitates which is removed by filtration. Washing this material several times with water affords 2-(4-chlorophenyl)-4,6-(1H,5H)-pyrimidinedione.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:40][CH3:41])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc21
Yield: 47.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.05 g (0.18 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic layers were washed with brine, dried, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.040 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-159).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:29][C:30](OC(C)=O)=[O:31].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[CH2:2][NH:1][C:30](=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)[C@@H](C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of (S)-(5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-phenyl)-methanol (0.0914 g, 0.24 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.0228 mL, 0.24 mmol), Et3N (0.05 mL, 0.36 mmol), and KI (0.0033 g, 0.02 mmol), and stirred at room temperature for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0750 g (64%) of COMPOUND 401 as a white solid. 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.6 Hz), 1.71 (s, 2H), 1.99 (s, 3H), 2.05 (s, 3H), 3.63-3.77 (m, 2H), 3.81-3.96 (m, 2H), 4.02-4.09 (m, 1H), 4.20-4.29 (m, 2H), 4.37 (d, 2H, J=5.4 Hz), 5.76 (s, 1H), 6.87 (s, 1H), 7.04-7.23 (m, 3H), 7.33-7.39 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.38 (d, 2H, J=3.9 Hz), 8.57 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 11.93, 18.45, 23.58, 43.70, 52.43, 53.86, 58.92, 63.32, 122.57, 122.67, 124.03, 127.44, 130.86, 132.10, 132.86, 136.70, 137.05, 138.55, 142.57, 146.56, 148.93, 156.59, 161.08, 170.41. ES-MS m/z 441.4 (M+Na). Anal. Calcd. for C25H30N4O2.0.8CH2Cl2.0.8H2O: C, 63.70; H, 6.55; N, 11.52. Found: C, 63.76; H, 6.56; N, 11.60.
Reaction SMILES: CN(C)CCNC.BrC1SC(C=O)=CC=1.[CH3:16][N:17]([CH3:29])[CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:26]/[C:24]2[S:25][C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:29])[CH3:16])[CH3:28])=[CH:22][CH:23]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CN(C)CCN(C)c1ccc(C=O)s1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CNCCN(C)C
Agent: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(N(C)CCN(C)C)s2)cc1OC
Yield: 32.3 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from N,N,N′-trimethylethylenediamine (6.13 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-[(2-dimethylamino-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (yield: 3.26 g, 77%). The produced 5-[(2-dimethylamino-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (2.12 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.77 g) through Method A (production step 2), to thereby yield the target product (yield: 1.20 g, 32%).
Reaction SMILES: [C:1]([C:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=1)([CH3:6])[CH3:5])([OH:3])=O.[N:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)=[C:19]=[S:20].C(N(CC)CC)C>CCO>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:18]2[C:1](=[O:3])[C:4]([CH3:6])([CH3:5])[N:7]([C:8]3[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=3)[C:19]2=[S:20])=[CH:22][C:23]=1[C:29]([F:30])([F:31])[F:32])#[N:26]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(Nc1ccc(C(=O)O)c(F)c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 2.2 %

Procedure:
4-(1-Carboxy-1-methyl-ethylamino)-2-fluoro-benzoic acid (241 mg, 1 mmol), 4-isothiocyanato-2-trifluoromethylbenzonitrile (342 mg, 1.5 mmol) and triethylamine (343 mg, 3.4 mmol) were mixed in EtOH (5 mL) and the solution was stirred for 10 days at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1M aqueous HCl, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography eluting with ethyl acetate to obtain 4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-benzoic acid (10 mg) as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([NH:7][NH2:8])=O)[CH3:2].[C:10](=[S:12])=[S:11].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:11][C:10]([SH:12])=[N:8][N:7]=1)=[O:9])[CH3:2]
Reactant: S=C=S
Reactant: CCOC(=O)C(=O)NN
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1nnc(S)s1
Temperature: 55 °C

Procedure:
Scheme 1 shows a synthetic method that may be used to prepare compounds of formula I-III. First, hydrazino-oxo-acetic acid ethyl ester 1 (prepared by the method of Berdinskii, I. S.; Maslivets, A. N. Hydrazides of disubstituted glycolic acids. Zh. Org. Khim. (1982), 18(9), 1839-43) is treated with carbon disulfide (excess) and KOH (1.0 equiv.) in ethanol at 0° C. to give 2. Treatment of 2 with cold (excess) sulfuric acid for 20 minutes followed by heating to 55° C. for 1 hour gives 5-mercapto-[1,3,4]-thiadiazole-2-carboxylic acid ethyl ester which is then treated with ethyl iodide and potassium carbonate in ethanol/water at room temperature to give 3. Heating compound 4 in the presence of benzylamine gives the amide, which is oxidized to the sulfone 5 with m-chloroperbenzoic acid (2.5 equiv) in chloroform or methylene chloride at room temperature. Treatment of 5 with 3-oxo-pentanoic acid methyl ester and excess sodium hydride in refluxing tert-butanol for 48 hours gives 6 after flash silica purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[OH:11][CH:8]([C:4]1[CH:3]=[C:2]([NH:1][C:27](=[O:28])[O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:9][OH:10]
Reactant: Nc1cccc(C(O)CO)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(C(O)CO)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
1-(3-Aminophenyl)ethane-1,2-diol (10 g) was dissolved in DCM (80 mL). H2O (80 mL) and Na2CO3 (10.98 g) were added and the mixture cooled to 0° C. Benzylchloroformate (22 g) was added drop-wise over 20 minutes and the reaction mixture stirred at room temperature overnight. The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (8 g, 45%).
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[NH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([NH2:22])=[C:14]([Cl:23])[CH:13]=1)[C:8]([OH:10])=[O:9]>O.C1COCC1>[NH2:22][C:15]1[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]([CH2:11][C@@H:7]([NH:6][C:1]([O:4][C:12]([CH3:17])([CH3:13])[CH3:11])=[O:2])[C:8]([OH:10])=[O:9])=[CH:13][C:14]=1[Cl:23]
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.71 g (35.0 mmol) of NaHCO3 in 100 mL water was added to a solution of 6.5 g (23.0 mmol) of (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 140 mL of THF. 15.28 g (70.0 mmol) of Boc-anhydride was added and the mixture was stirred for 3 h at RT. THF was evaporated off i. vac., the aqueous phase was washed with EtOAc and acidified with 10% citric acid solution. The aqueous phase was exhaustively extracted with EtOAc, the combined org. extracts were dried over Na2SO4 and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:18]([C:19](=[O:21])[CH3:20])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Product: COc1cc(C=C(C(C)=O)C(C)=O)cc(OC)c1OC
Reaction time: 8 h

Procedure:
3-(3,4,5-trimethoxybenzylidene)-2,4-pentanedione (hereinafter “HSS”) was prepared by the condensation of 3,4,5-trimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of HSS is about 68% with a purity, as determined by GC, of 99.1%. HSS is an off-white free-flowing powder with a melting point of 83-86° C. with a λmax at 319 nm.