Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:36]=[CH:35][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:35][CH:36]=2)[CH2:3]1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](N)C2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1CCN(c2ccc(C(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.5 %

Procedure:
To a solution of 404 (0.295 g, 0.601 mmol) in pyridine (3.0 mL) under nitrogen was added acetic anhydride (1.59 mL, 16.84 mmol), and the mixture was stirred for 19 h at room temperature. The solvent was evaporated and the residue obtained was evaporated twice with toluene and triturated with a mixture of Et2O and hexanes. The solid was filtered, air-dried and then dried under vacuum to afford the title compound 407 as a light pink solid (280 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[C:12]=1[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10].C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CS(C)=O>[Cl:29][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][CH3:37])=[C:13]([O:18][CH3:19])[C:12]=1[O:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10]
Reactant: COc1c(O)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OCCc2ccccc2)c1OC
Reaction time: 48 h

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-2-phenethyloxy-phenyl)-ethanone obtained from example 112 (89.3 mg, 0.1 mmol) was treated with piperidine (0.8 mL) and water (0.32 mL). The yellow suspension was heated to 90° C. for 54 hours. The solvent was evaporated in vacuo. The crude mixture was treated with NH4Cl (sat., 1 mL) and the organic products were extracted with EtOAc (3×2 mL). The combined organic phases was dried over Na2SO4 and evaporated in vacuo. Purification by flash chromatography using a gradient of EtOAc in toluene as eluent provided 2-(3,5-dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone as a white solid. Yield 8.6 mg (20%). 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone (5.5 mg, 0.013 mmol) was dissolved in DMSO (0.45 mL) and treated with K2CO3 (0.019 mL of a 1M aq. solution) followed by ethyliodide (0.019 mL of a 1M solution in DMSO). The reaction mixture was left at rt for 48 hours and purified by standard HPLC purification. 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-ethoxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone was obtained as a colourless solid. Yield 3.2 mg (36%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of Boc-L-Lys(Z)OMe 31 (2.00 g, 12.6 mmol) in DCM (30 mL) was added 30 mL of TFA. The mixture was stirred at rt for 1 h. Then the solvent were removed in vacuo, the residue was coevaporated 3 times with toluene. The residue was precipitated in Et2O to give the subject compound (2.1 g, yield 100%). Intermediate 32 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.45 (sl, 2H), 7.33 (m, 5H), 7.31 (t, 1H), 5.00 (s, 2H), 4.03 (m, 1H), 3.74 (s, 3H), 2.97 (m, 2H), 1.75 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].O.[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34]Br)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12]>CC(C)=O.C(OCC)(=O)C.CN(C=O)C>[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34][O:6][C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)(C)C
Yield: 87.3 %

Procedure:
In 20 ml of acetone is dissolved 0.61 g of pivalic acid, and 3.0 ml of 2N-NaOH and 10 ml of water are added. And then, 1.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 30 ml of DMF are added and the mixture is refluxed for 6 hours. After cooling, 150 ml of ethyl acetate is added and the organic layer is separated. The aqueous layer is is further extracted with 50 ml of ethyl acetate. The organic layers are combined, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 400 ml of diisopropyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.1 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[S:24]1[CH:28]=[CH:27][N:26]2[CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=[C:25]12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32]([C:30]2[N:31]=[C:25]3[N:26]([CH:29]=2)[CH:27]=[CH:28][S:24]3)=[O:33])=[O:10])[N:12]=1
Reactant: O=C(O)c1cn2ccsc2n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn3ccsc3n2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Imidazo[2,1-b]thiazole-6-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=478.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][C:36]1[S:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>CN(C=O)C>[CH3:35][C:36]1[S:37][C:38]([S:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[C:17]=3[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]2)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)s1

Procedure:
Compound A32 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), 2,4-dimethyl-thiazole-5-sulfonyl chloride (10 mg, 0.047 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.09 (m, 4H), 2.67 (s, 3H), 2.75 (s,3H), 3.08 (s, 3H), 3.21 (m, 2H), 3.50 (m, 2H), 5.58 (m, 1H), 7.85 (d,2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C21H24N6O7S3 568.09, found 569.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[S:12][CH2:13][CH2:14][N:15]=1.[H-].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:11]1[S:12][CH2:13][CH2:14][N:15]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(CNC2=NCCS2)c1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cccc(C)c1C)C1=NCCS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Under a dry nitrogen atmosphere, a solution of 0.25 gram (0.0011 mole) of ((2,3-dimethylphenyl)methyl)-1,3-thiazolin-2-ylamine dissolved in 10 mL of THF was added to a stirred suspension of 0.08 gram (0.0012 mole) of sodium hydride (60% suspension in oil). The mixture was stirred for 30 minutes, at which time a solution of 0.11 mL (0.0014 mole) of methyl chloroformate in 5 mL of THF was added slowly. The reaction mixture stirred at ambient temperature for about 18 hours. The reaction mixture was heated to 60° C. where it stirred for one hour. The reaction mixture was diluted with 25 mL of brine, then extracted with two 25 mL portions of ethyl acetate. The extracts were combined, washed with 25 mL of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to leave a solid residue. Analysis of the residue by TLC indicated that two compounds were present. The residue was purified by column chromatography on silica gel, eluting with hexanes:methylene chloride (1:1). The appropriate fractions were combined and concentrated under reduced pressure to yield 0.05 gram of methyl 2-(1-aza-2-(2,3-dimethylphenyl)ethylidene)-1,3-thiazolidine-3-carboxylate (Compound C53) and 0.14 gram of N-((2,3-dimethylphenyl)methyl)methoxy-N-(1,3-thiazolin-2-yl)carboxamide (Compound D5). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH:15]([CH3:19])[C:16](O)=[O:17])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[S:14][CH:15]([CH3:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Sc1nc(SCc2ccccc2)n[nH]1)C(=O)O
Solvent: CCOC(C)=O
Product: CC1Sc2nc(SCc3ccccc3)nn2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The product of stage (a) (57.9 g) was added portionwise to polyphosphoric acid (250 ml) at about 100° C. with stirring. Heating was continued for 30 minutes and the solution was then added to ice-water (1 l) and ethyl acetate (300 ml). The ethyl acetate solution was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with aqueous bicarbonate and water, dried and run down to give 49.3 g of crude product. Recrystallisation from ethanol gave 45.1 g of desired product, mp 85°-87° C.
Reaction SMILES: C([CH:8]([O:12][CH2:13][CH2:14][O:15]C1CCCCO1)[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](S(O)(=O)=O)=[CH:27][CH:28]=1>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:8][C:9]([O:11][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])C(Cc1ccccc1)OCCOC1CCCCO1
Solvent: CO
Product: O=C(COCCO)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of THP-protected hydroxy ester 3 (2 g, 6.8 mmol) in methanol (80 ml) was added p-TsOH (80 mg, 1 mg/ml). The reaction mixture was stirred at room temperature for 45 nm, concentrated and diluted with EtOAc. Organic layer was washed twice with NaHCO3 and water, dried over MgSO4, filtered and concentrated. The obtained residue was either used without further purification for next step or, if needed, purified by flash chromatography on silica gel (EtOAc/pentane 1/1) to give hydroxy ester 4 as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccc(Cl)cc2)n1
Temperature: 110 °C
Yield: 102.4 %

Procedure:
N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino} ethyl)acetamide (1.00 g) and piperazine (2.66 g) were dissolved in DMSO (40 ml) and sodium hydrogencarbonate added (1.29 g). The mixture was heated to 110° C. for 6 hrs. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was washed further with ethyl acetate (2×100 ml) and the combined organics subsequently washed with saturated brine solution (50 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (1.18 g).
Reaction SMILES: C([O:4][C:5]1[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][C:8]([CH:9]=[C:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]#[N:19])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[S:11]2)=[CH:7][C:6]=1[CH:29]([CH3:31])[CH3:30])(=O)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].Cl.[Cl-].[Na+]>CC(C)=O>[OH:4][C:5]1[C:6]([CH:29]([CH3:31])[CH3:30])=[CH:7][C:8]([CH:9]=[C:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[NH:34][N:33]=[N:32][N:19]=3)[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[S:11]2)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Oc1c(C(C)C)cc(C=C2Sc3ccccc3N(CC#N)C2=O)cc1C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)C)c1O
Temperature: 105 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 2-(4-acetoxy-3,5-diisopropylbenzylidene)-4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (compound No. 1-3, 0.47 g) in dimethylformaldehyde (5 ml), sodium azide (0.21 g) and ammonium chloride (0.17 g) were added. The mixture was stirred overnight at 105° C. under a nitrogen atmosphere. To acidify the mixture, 1N hydrochloric acid was added. Saturated sodium chloride solution was added to the mixture and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. To the residue, 1N aqueous sodium hydroxide solution was added and the whole was washed with diethyleter. 5.8N hydrochloric acid was added to the aqueous layer to acidify it and the whole was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.36 g (76.4%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.[C:18]([NH2:21])(=[S:20])[CH3:19]>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:18]([CH3:19])[S:20][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:17]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc([N+](=O)[O-])c1
Product: COC(=O)c1nc(C)sc1-c1cccc([N+](=O)[O-])c1

Procedure:
prepared by reaction of 3-chloro-3-(3-nitro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=279.3.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][C:37]1[CH:38]=[C:39]2[C:43](=[C:44]([NH:46][S:47]([C:50]3[S:51][CH:52]=[CH:53][CH:54]=3)(=[O:49])=[O:48])[CH:45]=1)[NH:42][C:41]([C:55]([NH:57][CH2:58][CH2:59][S:60]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:40]2.C(=O)([O-])O.[Na+]>ClCCl>[S:60]1[CH2:59][CH2:58][N:57]=[C:55]1[C:41]1[NH:42][C:43]2[C:39]([CH:40]=1)=[CH:38][C:37]([CH3:36])=[CH:45][C:44]=2[NH:46][S:47]([C:50]1[S:51][CH:52]=[CH:53][CH:54]=1)(=[O:49])=[O:48]
Reactant: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C3=NCCS3)cc2c1
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
A mixture of triphenylphosphine oxide (2.6 g), trifluoromethanesulfonic anhydride (0.80 mL) and dichloromethane (25 mL) was stirred for 15 min under ice-cooling. 5-Methyl-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (1.0 g) was added, and the mixture was stirred for 2 hr under ice-cooling. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (528 mg, yield 89%) as colorless prism crystals. melting point 202-203° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](O)=[O:15])[CH:5]=[CH:4][C:3]1=2.[I:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.CCN(CC)CC.[NH4+].[Cl-]>O=S(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:21][CH:20]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(I)cc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2 (1.38 g, 5.94 mmol) was dissolved in SOCl2 and two drops of DMF were added at 0° C. The mixture was stirred at 0° C. for 30 min and it was evaporated and this crude product was dissolved in CH2Cl2 (5 mL). B) 4-iodophenylamine (1.30 g, 5.94 mmol) and DMAP (73 mg, 0.59 mmol) were dissolved in CH2Cl2 (10 mL) and Et3N (8.4 mL) was added at 0° C. The Mixture A) was added in B) at 0° C. via syringe and the resulting mixture was stirred at 0° C. for 10 min and abandoned at RT for 2.5 h. A solution of aqueous NH4Cl 5% (50 mL) was added and the resulting mixture was extracted with EtOAc (3×150 mL). The organic layer was washed with NaHCO3 (2×100 mL) and brine (3×100 mL) and dried with MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane:EtOAc=90:10. 5,6,7,8-Tetrahydro-N-(4-iodophenyl)-5,5,8,8-tetramethylnaphthalene-2-carboxamide 22 was obtained (1.43 g, 56% yield) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37](=[O:39])[NH2:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([NH2:38])=[O:39])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: NC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(N)=O)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[carbamoylmethyl]piperazine hydrochloride
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH3:16])[C:5]([C:14]#[N:15])=[C:6]2[C:10]=1[O:9][C:8]([CH:11]1[CH2:13][CH2:12]1)=[N:7]2.[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:35][CH2:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:14]([C:5]1[C:6]2[N:7]=[C:8]([CH:11]3[CH2:12][CH2:13]3)[O:9][C:10]=2[C:2]([C:33]2[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:32]=2)=[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:16])#[N:15]
Reactant: Cc1c(-c2ccccc2)c(Br)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(NC(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)c(C2=CC(NC(=O)OC(C)(C)C)CC2)c2oc(C3CC3)nc2c1C#N
Yield: 75.8 %

Procedure:
A 1,4-dioxane (6 ml) solution of 7-bromo-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-46) (89 mg, 0.252 mmol), 1-(N-tert-butoxycarbonylamino)-3-tri-n-butylstannyl-2-cyclopentene (143 mg, 0.302 mmol), bis(triphenylphosphine)palladium(II) chloride (8.8 mg, 0.0126 mmol), 2,6-di-tert-butyl-p-cresol (5.6 mg, 0.0252 mmol) was refluxed overnight. After cooling, the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→8:1→5:1) to obtain the entitled compound (87 mg, 75%) as a pale brown solid.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[C:12]2[C:16](=O)[O:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13]2)=[CH:6][C:5]=1[CH2:24][O:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29]>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][C:12]([C:16]([NH2:1])=[O:15])=[N:11]2)=[CH:6][C:5]=1[CH2:24][O:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29]
Reactant: O=C1OC(c2ccccc2)=NC1=NNc1ccc(Cl)c(COCC(F)(F)C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(-c2ccccc2)n(-c2ccc(Cl)c(COCC(F)(F)C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 100.7 %

Procedure:
A 29% ammonia aqueous solution (3.48 kg, 59.2 mol) was added to 47.8 kg of water. 2-phenyl-4,5-oxazoledione 4-[4-chloro-3-(2,2,3,3,3-pentafluoropropoxy)methylphenyl]hydrazone (14.9 kg, purity: 94.4%, water content: 36.5%, 19.4 mol) was added to the solution and the mixture was heated while stirring. After heating at 80° C. for two hours (after three hours after initiation of the heating), the reaction mixture was cooled to 50° C. and filtered by centrifugation. The residue was washed with hot water dried in a hot air drier to obtain 9.0 kg of the target compound.