Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.C([Si]([O:71]/[C:72](/[C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[CH:85][CH:84]=2)=[CH:77][CH:76]=1)=[CH:73]\[CH3:74])(C)C)(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[OH:22][C@H:73]([CH3:74])[C:72]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[CH:85][CH:84]=2)=[CH:77][CH:76]=1)=[O:71]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(COc2ccc(C(=O)[C@@H](C)O)cc2)cc1
Yield: 89 %

Procedure:
Ad-mix-β (28.0 g) and methanesulfonamide (1.90 g, 20 mmol) were suspended in t-butanol (100 mL) and water (100 mL), then the compound (7.7 g, 20 mmol) synthesized in the above (2) was added under stirring with cooling with ice. The reaction solution was stirred for 15 hours with cooling with ice, then sodium sulfite (20 g, 0.16 mol) was added, and further stirred at room temperature for 1 hour. The reaction solution was poured in water, extracted with chloroform, and the organic layer was washed with saturated ammonium chloride and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with diisopropyl ether and n-heptane to obtain the entitled compound (5.1 g, 89%) as a milky white solid.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=O.C1(C)C=CC=CC=1.[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=2)[NH:23]C(=O)[C:21]1=[O:47])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[ClH:3].[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=2)[N:23]=[C:1]([Cl:4])[C:21]1=[O:47])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cn(-c2cc3[nH]c(=O)c(=O)n(OCc4ccccc4)c3cc2C(F)(F)F)c(-c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc3nc(Cl)c(=O)n(OCc4ccccc4)c3cc2C(F)(F)F)c(-c2ccccc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of 20% phosgene in toluene (18.2 ml, 35 mmol) was added dropwise to a stirred solution of 1-benzyloxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione (8.8 g, 17.5 mmol) in 100 ml of dry N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature overnight and the precipitated solid was isolated by filtration and washed with ether to give 8.0 g (84%) of the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[S:11][C:12]2[C:18](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O>CS(C)=O>[CH3:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.1 %

Procedure:
To a suspension of 60% sodium hydride (0.600 g, 15.6 mmol) in dimethyl sulfoxide (10 mL) was added a solution of trimethylsulfoxonium iodide (3.44 g, 15.6 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl-1,3-benzothiazol-7-yl)acrylate (1.60 g, 6.47 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.62 g, yield 69%).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([NH:21][CH2:18][CH2:19][CH3:20])=[C:8]1[C:9]#[N:10]
Reactant: CCCN
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: CCCNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 224 mg (3.80 mmol) of n-propylamine to give 14 mg (13% of theory) of the title compound.
Reaction SMILES: [Br:1]Br.[S:3]1[C:11]2[C:6](=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:5]1[C:6]2=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[S:3][CH:4]=1
Reactant: BrBr
Reactant: COC(=O)c1cc2sccc2nc1C(=O)OC
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2scc(Br)c2nc1C(=O)OC
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of bromine (20 g, 0.125 mol) in acetic acid (50 mL) is added dropwise over three hours to a solution of dimethyl thieno[3,2-b]pyridine-5,6-dicarboxylate, (26.3 g, 0.104 mol), containing sodium acetate (17.2 g, 0.2 mol) in acetic acid (300 mL) at 85° C. Additional sodium acetate (18 g) and bromine (20 g) in acetic acid (50 mL) is added over an hour and the mixture stirred at 85° C. overnight. Bromine (10 g) is added in one portion then left at 85° C. for four hours. The mixture is cooled and treated with aqueous sodium bisulfite, diluted with ethyl acetate and concentrated. The reaction product is partitioned between water and methylene chloride and the organic layer washed with aqueous sodium chloride and the solvent removed. The residue is washed with ether to give 25 g of crude product, mp 165°-168° C. Recrystallization from methanol gave needles of dimethyl 3-bromothieno[ 3,2-b]pyridine-5,6-dicarboxylate, mp 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](=[O:13])(O)[O-].[CH3:14]O>S(Cl)(Cl)=O>[CH3:14][O:7][CH:6]([O:13][CH3:10])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=C([O-])O
Reactant: CO
Reactant: O=Cc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: COC(OC)c1ccc(Br)cc1

Procedure:
50 g of 4-bromobenzaldehyde and 30 ml of o-triethyl formate are agitated for 5 hours at room temperature in 60 ml of methanol and 0.8 ml of thionyl chloride. After that, another 0.2 ml of thionyl chloride are added. The batch is poured into aqueous bicarbonate solution after 30 minutes and extracted with chloroform, washed with aqueous bicarbonate solution and water, dried above sodium sulfate, and concentrated by evaporation under reduced pressure. 68 g of 4-bromobenzaldehyde dimethyl ketal are obtained in the form of colourless oil.
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH:10]([NH2:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:8])=[O:7])(C)(C)C.FC1C=CC=C(F)C=1O[C:23]1[O:24][C:25]([CH3:34])([CH3:33])[C:26]([CH3:32])([CH3:31])[S:27](=[O:30])(=[O:29])[N:28]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([NH:18][C:23]2[O:24][C:25]([CH3:34])([CH3:33])[C:26]([CH3:32])([CH3:31])[S:27](=[O:30])(=[O:29])[N:28]=2)[CH2:9][S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)NS(=O)(=O)CC(N)c1ccc(F)cc1
Reactant: CC1(C)OC(Oc2c(F)cccc2F)=NS(=O)(=O)C1(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(NC(CS(N)(=O)=O)c2ccc(F)cc2)=NS(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
50 mg of N-(tert-Butyl)-2-amino-2-(4-fluorophenyl)ethanesulfonamide enantiomer 1 and 58 mg of 2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide were dissolved in 1 ml of dichloromethane, and the mixture was stirred at room temperature for 5 hours. The completeness of the conversion was checked by LCMS. Since no conversion had taken place yet, 60 μl of N,N-diisopropylethylamine were added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 20 ml of ethyl acetate and washed with 10 ml of 0.1 N hydrochloric acid and 10 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 1 ml of trifluoroacetic acid and dissolved at room temperature for 20 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (25.8 mg) was obtained with a molecular weight of 407.5 g/mol (C15H22FN3O5S2); MS (ESI): m/e=408 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:21]([C:17]1[O:16][CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C(Cl)c1ccco1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CN(C)CCN(C(=O)c1ccco1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and furan-2-carbonyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([N:24]([CH2:27][CH3:28])CC)C.[O:29]1[CH2:34][CH2:33]C(CO)[CH2:31][CH2:30]1.O>C1(C)C=CC=CC=1>[O:29]1[CH2:34][CH2:33][CH:28]([CH2:27][NH:24][C:19]([C:12]2[C:13]([C:15]([F:18])([F:16])[F:17])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][CH:11]=2)=[O:21])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: CCN(CC)CC
Reactant: OCC1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCC1CCOCC1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (300 mg), triethylamine (197 μL), and toluene (6 mL) was added dropwise diphenyl phosphoric acid azide (265 μL), followed by stirring at room temperature for 30 minutes. Then, the mixture was stirred at 90° C. for 10 minutes, and a solution of tetrahydro-2H-pyran-4-yl methanol (131 mg) in toluene was added thereto, followed by heating with reflux for 2 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained pale yellow solid was washed with ethyl acetate-hexane to obtain tetrahydro-2H-pyran-4-ylmethyl {2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}carboxamide (178 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C>[NH:3]1[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:6][N:5]=[N:4]1
Reactant: O=C(O)CCCCCCCCCCCI
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCc1nnn[nH]1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A suspension of NaH (0.045 g, 80% suspension in oil) in DMF (1 ml) was added to a solution of tetrazole 44 (0.095 g, 1.35 mmmol) in DMF (1 ml). After stirring the reactants for 15 min, a solution of 12-iodo-dodecanoic acid 45 (0.2 g, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 1 h and at 55° C. for 1.5 h and then concentrated in vacuo. The residue was treated with 1N HCl(5 ml) and extracted with EtOAc (2×10 ml). The organic layer was washed with water, dried (Na2SO4), concentrated under reduced pressure and the residue was crystallized from EtOAc/Hexane to give the title compound 46 (0.095 g, 26%) as a 1:3 mixture of N-3 and N-1 isomers, respectively. This mixture was tested directly as a substrate for NMT. 1H NMR (CDCl3) δ: 8.59 and 8.5 (2s, 1H); 4.65 and 4.43 (2t, 2H, J=7.2 Hz); 2.35 (t, 2H, J=7.5 Hz); 1.95 (m, 2H); 1.63 (m, 2H); 1.26 (m, 14H). FABMS: m/z 269 (M+H); 251 and 241. HRMS: m/z=C13H24N4O2Li, calc: 275.2059, found: 275.2004 (M+Li).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:26][CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccc(-n2cccn2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(Cl)cc1
Temperature: -76 °C
Reaction time: 0.08 h
Yield: 38.9 %

Procedure:
In a dry flask, 2,2,6,6-tetramethylpiperidine (0.30 mL, 1.8 mmol) in anhydrous THF (10 mL) under argon was treated with a 1.6M solution of n-butyllithium in hexanes (1.1 mL, 1.8 mmol) at −76° C. during 2 minutes. After stirring for 5 minutes at −76° C., a solution of 1-(4-chlorophenyl)-1H-pyrazole (0.21 g, 1.1 mmol) in anhydrous THF (2 mL) was added over 4 minutes. After stirring for 20 minutes at −76° C., tributyltin chloride (0.30 mL, 1.11 mmol) was added all at once. The resulting mixture was stirred at −76° C. for 10 minutes and at ambient temperature for 5 minutes, then quenched by addition of methanol (1 mL). The mixture was concentrated by rotary evaporation, the residue was taken up in water (20 mL) and washed with ethyl acetate (20 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. Purification of the crude product by flash chromatography on silica with ethyl acetate/n-heptane (1:7) as eluent gave 1-(4-chlorophenyl)-5-tributylstannyl-1H-pyrazole (0.20 g, 40%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[C:10]([OH:13])(=[S:12])[CH3:11]>>[C:10]([S:12][CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4]([OH:6])=[O:5])(=[O:13])[CH3:11]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CC(O)=S
Product: CC(=O)SCC(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 50 mL round bottom flask was added 2-(trifluoromethyl)acrylic acid (6 g, 42.8 mmol), followed by thioacetic acid (4.59 ml, 64.3 mmol). The reaction was slightly exothermic. The mixture was then stirred at 25° C. overnight. NMR showed some starting material (˜30%). One more equiv of thioacetic acid was added and the mixture was heated at 95° C. for 1 hour, then allowed to cool to room temperature. Mixture was purified by vacuum distillation at 2.1-2.5 mm Hg, fraction distilled at 80-85° C. was mostly thioacetic acid, fraction distilled at 100-110° C. was almost pure product, contaminated by a nonpolar impurity (by TLC). It was again purified by flash chromatography (0-20% MeOH/DCM), to give 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (7.78 g, 36.0 mmol, 84% yield) as colorless oil, which solidified under high vacuum to give a white solid: mp 28-30° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (brs, 1H), 3.44 (dt, J=7.5, 3.5 Hz, 2H), 3.20 (dd, J=14.9, 11.1 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.79, 171.14, 123.44 (q, J=281.6 Hz), 50.47 (q, J=27.9 Hz), 30.44, 24.69 (q, J=2.6 Hz); 19F NMR (376 MHz, CDCl3) δ −67.82.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.36 ml (5 mmol) of propionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1:1→1:2→1:4) to yield 1.37 g (75.8%, light orange oily substance) of the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:15])[C:9]([SH:14])=[CH:10][CH:11]=[CH:12][CH:13]=1.F[C:17]1[CH:22]=[C:21]([Br:23])[C:20]([Br:24])=[CH:19][C:18]=1F.ClCCl>CN(C=O)C>[Br:24][C:20]1[C:21]([Br:23])=[CH:22][C:17]2[S:15][C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:14][C:18]=2[CH:19]=1
Reactant: Fc1cc(Br)c(Br)cc1F
Reactant: Sc1ccccc1S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1cc2c(cc1Br)Sc1ccccc1S2
Temperature: 80 °C
Yield: 58 %

Procedure:
To a solution of triethylamine (0.1 mL) in 10 mL DMF, 1,2-benzenedithiol (272 mg, 1 mmole) in 1 mL DMF and 1,2-difluoro-4,5-dibromobenzene (171 mg, 1.2 mmole) in 1 mL DMF was slowly added separately at the same time with continued stirring and under Ar. The reaction mixture was heated at 80° C. for over night. The solution was then turned dark yellow. The reaction mixture was cooled and poured into dichloromethane (50 mL). The organic layer was further washed with 1N HCl and water (twice), dried by MgSO4, and the solvent was removed in vacao. The crude product was further purified by column chromatography (hexane/dichloromethane 6/1) to yield white solids (217 mg, 58%). mp 160˜161° C. 1H NMR (300 MHz, CDCl3) δ: 7.67 (s, 2H), 7.40 (dd (AA′XX′), 2H, JAX=5.7 Hz and JAX′=3.3 Hz), 7.24 (dd (AA′XX′), 2H, JAX=3.3 Hz and JAX′=2.7 Hz). 13C NMR (75 MHz, CDCl3) δ: 136.4, 134.4, 132.3, 128.8, 128.0, 123.6. FT-IR (KBr)v/cm−1: 3059, 1451, 1429, 1304, 1106, 1056, 879, 826, 746, 662, 576, 473, 441. HR-MS (EI): calcd. for Cl2H6Br2S2 371.8272 [M+]. Found 371.8283.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[O:20][CH3:21])[CH:3]=1
Reactant: O=Cc1cc(Cl)c(Cl)cc1F
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C=O
Temperature: 70 °C
Yield: 51 %

Procedure:
Crude 4,5-dichloro-2-fluoro-benzaldehyde, 4-fluoro-2-methoxy-phenol (2.31 mL, 20.23 mmol) and K2CO3 (5.59 g, 40.46 mmol) were combined in DMF (100 mL) and heated for ˜30 min at 70° C., then at 55° C. overnight. The reaction was cooled, diluted with water (500 mL) and extracted with diethyl ether. The ether layer was dried over Na2SO4, filtered, and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexane (0-40%) provided 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde (3.30 g, 51%) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.93 (s, 1H), 7.35 (dd, J=8.8, 5.8 Hz, 1H), 7.19 (dd, J=10.7, 2.9 Hz, 1H), 6.92-6.85 (m, 2H), 3.78 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:11]=[CH:12][C:13](=[O:16])[CH:14]=[CH:15]2)=[CH:6][CH:5]=1
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2ccc(=O)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 10 g 1-(4-Nitro-phenyl)-1H-pyridin-4-one in 510 mL ethyl acetate and 26 mL ethanol, 52.1 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 6 h. Then, after cooling to RT the solvents were removed under reduced pressure. The residue was taken-up in 100 mL aqueous NaHCO3 solution and 200 mL ethyl acetate were added. The inorganic precipitate was filtered off and the solids were washed with ethyl acetate. After separation of the organic layer, the aqueous layer of the filtrate was extracted with ethyl acetate (2×100 ml) and with DCM (3×150 ml). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step. Yield: 6 g.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][C:17](=[O:64])[CH:18]([NH:33][C:34]([NH:36][CH:37]([C:52]([O:54]CC2C=CC(OC)=CC=2)=[O:53])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]2[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=2)=[O:35])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])=CC=1>C(O)(C(F)(F)F)=O>[C:52]([CH:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:64])=[O:16])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]1[CH:45]=[CH:46][C:47]([I:50])=[CH:48][CH:49]=1)([OH:54])=[O:53]
Reactant: COc1ccc(COC(=O)CCC(NC(=O)NC(CCCCNC(=O)c2ccc(I)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1ccc(I)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 3% anisole in TFA (15 mL) was added to 2 (0.117 g, 0.129 mmol) at 0° C. The mixture was stirred at room temperature for 30 min then concentrated on a rotary evaporator. The crude material was purified by HPLC (Econosil C18 10μ, 250×10 mm, H2O/CH3CN/TFA (70/30/0.1), 4 mL/min, 3 eluting at 11 min) to afford 0.040 g (57%) of 3. 1H NMR (400 MHz, D2O:CD3CN=1:1 (v/v)) δ 7.79 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.08-4.16 (m, 2H), 3.26 (m, 2H), 2.35 (m, 2H), 2.00-2.03 (m, 1H), 1.72-1.84 (m, 2H), 1.52-1.62 (m, 3H), 1.34-1.36 (m, 2H). ESI-Mass calcd for C19H24IN3O8Na [M+Na]+ 572.1, found 572.0. FAB-HRMS calcd for C19H25IN3O8 [M+H]+ 550.0686, found 550.0648.
Reaction SMILES: CS([C:5]1[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)(=O)=O.[C-:17]#[N:18].[K+]>CN(C=O)C>[NH2:14][C:11]1[N:9]2[N:10]=[C:5]([C:17]#[N:18])[C:6]([CH3:16])=[C:7]([CH3:15])[C:8]2=[N:13][N:12]=1
Reactant: Cc1c(S(C)(=O)=O)nn2c(N)nnc2c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C#N)nn2c(N)nnc2c1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
6-Methanesulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.130; 1.0 g) was dissolved in DMF (30 ml) and admixed with potassium cyanide (405 mg). After stirring at 100° C. for 1 h, the mixture was dried. The residue was stirred in EA and chromatographed using a short silica gel column with EA. Fractions concentrated by rotary evaporation. 560 mg of the title compound were obtained.