Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]=[O:32])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]([OH:32])[CH3:1])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methylmagnesium bromide in tetrahydrofuran (1 M, 54.3 ml) was added anhydrous tetrahydrofuran (90 ml). To the solution was added dropwise a solution of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-methoxy-2,4,5-trimethylphenyl)heptanoate (4.5 g, 10.9 mmol) in tetrahydrofuran (20 ml) at -78° C., followed by stirring for 30 minutes at the same temperature. To the reaction mixture, an aqueous solution of potassium hydrogensulfate, followed by subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate and water, in the order mentioned, and dried over magnesiumsulfate. The organic layer was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.4 g). Physico-chemical properties and spectral data of this compound are shown in [Table 5].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.BrC[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C=O)C.[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[C:23]1([C:29]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:14][CH2:13]3)=[CH:43][CH:44]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCCCN1CCCCC1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C2=C(c3ccc(OCCCN4CCCC4)cc3)Oc3ccccc3S2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Potassium carbonate (83 mg) and 1-(3-bromopropyl)piperidine hydrobromide (54.6 mg) were added to a DMF (3 mL) solution of 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol (63.7 mg, 0.2 mmol) obtained in Reference Example 1-1, and stirred at 80° C. for 8 hours. The reaction liquid was restored to room temperature, diluted with ethyl acetate, and extracted with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound (43.7 mg, 51%) as a yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[CH3:33][O:34][CH2:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:39]3[CH2:40][CH2:41][CH:36]([CH2:35][O:34][CH3:33])[CH2:37][CH2:38]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: COCC1CCC(=O)CC1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: COCC1CCC(N2CC(NC(=O)CNc3nn(CCO)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-methoxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([S:38][C:39](=[O:42])[CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C=O)C>[CH2:31]([S:38][C:39](=[O:42])[CH2:40][NH:41][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC(=O)SCc1ccccc1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCC(=O)SCc1ccccc1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
Biotin 19 (0.156 g, 0.64 mmol) was dissolved in 40 mL of dry THF. To this solution was added EDC (0.123 g, 0.64 mmol) and HOBt (0.098 g, 0.64 mmol) under ice-cold conditions. The reaction was allowed to stir for 30 minutes, followed by addition of 8 (0.139 g, 0.64 mmol) dissolved in minimal amount of DMF. The resulting solution was allowed to stir overnight at RT. Upon removal of the solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5 (0.110 g, 42%). 1H-NMR (300 MHz, DMSO) δ 7.31-7.28 (m, 5H), 6.40-6.35 (broad, 2H), 4.37-4.32 (m, 2H), 4.22 (d, J=5.61 Hz, 2H), 4.09 (s, 2H), 3.1-3.0 (m, 1H), 2.88-2.78 (m, 2H), 2.19-2.14 (m, 2H), 1.60-1.48 (m, 6H). MS (ESI): m/z 408.0 [(M+1)]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:12].N1C=CC=CC=1.C([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=O)C.Cl>CC(C)=O.CO.[OH-].[Na+]>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:12])[NH:11][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[OH:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1cc(Br)c(O)c(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)c(O)c(C(=O)O)c1)c1ccccc1O
Yield: 95.8 %

Procedure:
3-Bromo-5-aminosalicylic acid (0.73 g.) was dissolved in acetone (30 ml.) and pyridine (0.4 ml.) to which an acetone (14 ml.) solution containing acetyl-salicyloyl chloride (prepared from 0.53 g. of acetyl-salicylic acid) was added dropwise with stirring. After reaction the solution was evaporated to dryness under reduced and the residue was dissolved in ethyl acetate. After washing the solution with water and 1 N hydrochloric acid successively, the ethyl acetate was evaporated off under reduced pressure, yielding a residue which was redissolved in a mixture of methanol and 2 N sodium hydroxide (14 ml. each). After stirring the solution for several hours and then acidifying with 2 N hydrochloric acid solution, a precipitate was formed, collected and crystallized from aqueous methanol to give light brown crystals (0.90 g.) of 3'-bromo5'-carboxy-2,4'-dihydroxybenzanilide,
Reaction SMILES: C(N(CC)CC[N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](C=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])C.FC1C(F)=CC=CC=1C1C(F)=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[CH3:16][C:15]1[C:8]2[C:7](=[O:19])[NH:6][CH2:12][CH2:11][CH2:10][C:9]=2[NH:13][CH:14]=1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Agent: O=C1Cc2c(ccc(F)c2-c2cccc(F)c2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c[nH]c2c1C(=O)NCCC2
Temperature: 25 °C
Yield: 56 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (73 mg, 0.25 mmol) and 4-(2,3-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74 g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and added with 35 μl of piperidine to the solution at room temperature. Upon completion of the addition, the mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-5-(2-(diethylamino)ethyl)-2-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 74 (23 mg, yield 19%) as an orange solid.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][O:10][CH3:11])[C:3](OCC)=[O:4].C[O-].[Na+].[NH2:16][C:17]([NH2:19])=[NH:18].S(=O)(=O)(O)O>CN(C)C=O.C(O)C>[NH2:19][C:17]1[N:18]=[C:3]([OH:4])[C:2]([CH3:1])=[C:8]([CH2:9][O:10][CH3:11])[N:16]=1
Reactant: CCOC(=O)C(C)C(=O)COC
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COCc1nc(N)nc(O)c1C
Temperature: 20 °C
Yield: 26.6 %

Procedure:
Ethyl 2-methyl-3-oxo4-methoxybutyrate(10.5 g, 60 mmol) was added slowly to a suspension of sodium methoxide (6.5 g, 120 mmol) in dimethylformamide(10 ml) while maintaining the reaction temperature under 20° C. A solution of guanidine(5.7 g, 60 mmol) in ethanol was added to a reaction mixture, which was then refluxed for 5 hours, cooled to a room temperature, and neutralized with conc. sulfuric acid. The resulting solid was filtered and dried to give 2.7 g of the titled compound.
Reaction SMILES: CN1CCN(C)[C:4](=[O:9])[C:3]1=[O:10].[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[C:13]([Mg]Cl)[CH:12]=1>C1COCC1>[CH3:19][C:11]1[CH:16]=[C:15]([C:3]([C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH3:19])[CH:12]=2)=[O:9])=[O:10])[CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCN(C)C(=O)C1=O
Reactant: Cc1cccc([Mg]Cl)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C(=O)c2cccc(C)c2)c1
Yield: 35 %

Procedure:
Mueller-Westerhoff9 and co-workers reported a simple, high-yield two-step synthesis of symmetrically substituted α-diones. The first step involves the preparation of 1,4-dimethylpiperazine-2,3-dione (13). Compound 13 was prepared in high yield from the reaction between N,N′-dimethylethylenediamine and diethyl oxalate in anhydrous diethyl ether at room temperature overnight. Second, compound 13 reacts with 2 equivalents of organolithium or Grignard compounds to form symmetrically-substituted α-diones after hydrolysis. 3,3′-Dimethylbenzil was prepared from the reaction between compound 13 and 2 equivalents of m-tolylmagnesium chloride in dry THF, followed by acidic workup in 35% yield (not optimized). Bis[1,2-di(3-methylphenyl)ethane-1,2-dithiolene]nickel (17) was then prepared by Schrauzer and Mayweg procedure as shown in FIG. 8.10
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[C:13](#[N:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.S(=O)(=O)(O)O.[OH-:26].[NH4+].[CH3:28]O>C(Cl)(Cl)Cl.O>[OH:26][CH2:28][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]#[N:20]
Reactant: CO
Reactant: [OH-]
Reactant: N#Cc1ccncc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccnc(CO)c1
Reaction time: 24 h
Yield: 28 %

Procedure:
Add ammonium persulfate (70.1 g, 307 mmol) to a solution of isonicotinonitrile (16.00 g, 154 mmol) in methanol:water:sulfuric acid (275 mL:135 mL:11 mL). Heat solution to reflux. After 24 hours, pour reaction onto ice and neutralize with ammonium hydroxide (70 ml). Extract solution with chloroform (3×600 ml). Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone:dichloromethane (1:6) to yield the title compound as a white solid (5.86 g, 28%): 1H NMR (CDCl3) δ 3.17 (t, 1H), 4.84 (d, 1H), 7.45 (m, 1H), 7.58 (s, 1H), 8.74 (d, 1H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:14][C:15](=[N:17][OH:18])[CH3:16].O>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:18][N:17]=[C:15]([CH3:16])[CH3:14])(=[O:11])=[O:10]
Reactant: CC(C)=NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 16 h

Procedure:
To a solution of mesitylenesulfonyl chloride (2.0 g, 9.05 mmol) in pyridine (30 mL) was added acetone oxime (0.67 g, 9.05 mmol), and the solution was stirred under N2 for 16 hours. It was poured into 500 ml of water and stirred for 1 hour. The precipitate was filtered and dried Acetone O-(2,4,6-trimethylphenylsulfonyl)oxime was obtained as white powder (57.6%) yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8].CCN(CC)CC.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)c1sc(CO)cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)c1sc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reaction time: 14 h

Procedure:
A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q; 3.4 g, 14 mmol) in CH2Cl2 (4.0 mL) was treated with NEt3 (2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), and t-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture was stirred for 14 hours, then diluted with Et2O and washed with H2O. The organic layer was dried (MgSO4) and the solvent evaporated to provide the crude product, which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[SH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][S:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:10])=[O:9]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 10 h
Yield: 67 %

Procedure:
To a solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (450 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (150 mg) and methyl mercaptoacetate (130 μL), and the mixture was stirred at 50° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (348 mg, yield 67%) as pale-yellow crystals. melting point 126° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([O:15][CH:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH:16]([O:15][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(Cc1cccc(O)c1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(Cc1cccc(OC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C

Procedure:
Using ethyl 3-(3-hydroxyphenyl)-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH2:26]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:25][CH3:26])[C:9]1[S:10][C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO
Reactant: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1-c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N(CC)C(=O)OC(C)(C)C)sc1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate in THF were added EtOH, PPh3, and DEAD, followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2-[(tert-butoxycarbonyl) (ethyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(I)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 4-iodo-3-nitrobenzoic acid (0.286 g, 0.976 mmol) and thionyl chloride (5 ml) was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and Hunig's base (0.151 g, 1.17 mmol) in dry THF (10 ml) to give the title compound (0.403 g, 78%) as a yellow solid after work-up.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[C:4]([C:19]([NH:21][NH2:22])=[O:20])[CH:3]=1.O.[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O.O>C(O)(=O)C.C(OCC)(=O)C.O>[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[N:22][NH:21][C:19](=[O:20])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[N:5]=1
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: O=CC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1

Procedure:
4-methyl-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.38 g, 0.0012 mol) was dissolved in 5 ml of acetic acid. The obtained solution was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.40 g, 0.0012×2 mol), and then the resultant mixture was stirred at 80° C. for 3 hours. Thereafter, a chilled water was poured into the obtained reaction solution which was then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent from the dried product, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ncccc1-c1nn[nH]n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1-c1nnn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (100 mg) described in Manufacturing Example 5-1, 4-benzyloxybenzyl chloride (172 mg), sodium iodide (111 mg), and DMF (3 mL) was added NaH (18 mg), which was stirred for 40 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1, then 1:1). Ethyl acetate was added to the resulting residue, and the solids were filtered off to obtain the titled compound (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[S:22])[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared by heating under reflux overnight a mixture of 6-(3-chlorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(1H)-one and an equal weight of phosphorus pentasulfide in pyridine was stirred. Removal of the pyridine in vacuo followed by treating the residue with 6N hydrochloric acid and recrystallization of the residue in ethanol gave the product as a yellow solid: mp. 197-1980° C. 1H-NMR (DMSO-d6) δ 12.34 (s, 1H), 7.75 (m, 1H), 7.64 (m, 2H), 7.57 (dd, 1H J=9.3 and 2.1 Hz), 7.48 (t, 1H, J=7.7 Hz), 7.41 (m, 1H), 7.20 (d, 1H, J=8.3 Hz), 3.34 (s, 2H), 1.26 (s,6H); MS (APCI (−)) m/z 300 [M−H]− Anal. Calc. For C17H16ClNS: C, 67.65, H, 5.34, N, 4.64. Found: C, 67.77, H, 5.57, N 4.54.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][S:10][C:11]1[N:16]=[C:15]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][N:12]=1>>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:18]/[C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([S:10][CH3:9])[N:16]=1)=[O:19]
Reactant: CSc1nccc(C(C)=O)n1
Reactant: COC(OC)N(C)C
Product: CSc1nccc(C(=O)/C=C/N(C)C)n1
Yield: 69.4 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (9.87 mL, 74.3 mmol) was added to 1-(2-(methylthio)pyrimidin-4-yl)ethanone (0.50 g, 2.97 mmol). The mixture was heated at reflux overnight. The reaction mixture was concentrated to half volume and treated with Et2O. The resulting solid was collected by vacuum filtration to yield the desired (E)-3-(dimethylamino)-1-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one (0.46 g, 2.06 mmol, 69.3% yield).