Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:34]([NH2:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:44][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:5]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
5.0 g (20 mmoles) of Z-Pro-OH are dissolved in 50 ml of DMFA, 2.8 ml (20 mmoles) of triethylamine are added to the solution, and the mixture is cooled to -10° C. The mixture is stirred at the same temperature, 2.8 ml (21.5 mmoles) of isobutyl chloroformate are added dropwise, and after 10 minutes 4.4 ml (22 mmoles) of n-decylamine are introduced dropwise. After the addition the reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The resulting suspension is filtered, the filtrate is evaporated, and the residue is dissolved in 100 ml of ethyl acetate. The solution is shaken four times with 50 ml of n hydrochloric acid, each, twice with 50 ml of n sodium hydrocarbonate solution, each, and then with 50 ml of water, dried over anhydrous sodium sulfate and evaporated. The oily residue is crystallized from n-hexane to obtain 5.43 g (70%) of Z-Pro-NH-C10H21 ; m.p.: 78°-80° C., Rf2 =0.75.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: CCCCOc1ccc(S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 33 %

Procedure:
4-Butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-butoxybenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 98-100° C., yield 33%.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1cccc(F)c1)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cccc2NC(=O)[C@@H](N=[N+]=[N-])[C@H](c2cccc(F)c2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (134 mg, 0.42 mmol) and the product from step 4 (200 mg, 0.42 mmol) were dissolved in pyridine (4 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.46 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=683.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1>ClCCl>[C:8]([NH:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.76 ml, 5.45 mmol) and acetic anhydride (0.43 ml, 4.56 mmol) were added to an ice-cooled solution of tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem. 2001; 44(1); 94) (850 mg, 4.56 mmol) in dichloromethane (50 ml), and the reaction stirred for 30 minutes. The solution was washed with water (50 ml), brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluant to afford the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4](Cl)[N:3]=1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:17]2[CH2:18][CH2:19][CH2:16][CH2:15]2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: C1CCNC1
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of ethyl 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (3.00 g, 12.6 mmol: J. Med. Chem., 1986;29:2363) and triethylamine (2.63 mL, 18.90 mmol) in acetonitrile (15 mL) was added pyrrolidine (1.05 mL, 12.6 mmol) dropwise. After being stirred at 60° C. for 1 hour, the reaction mixture was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue was purified on a silica gel column using hexane/dichloromethane (7:3) as eluent giving 2.5 g of the title compound as a solid, mp 95° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione (50 g) dissolved in 100 ml of pyridine and 250 ml of acetic anhydride was swirled while being warmed on a steam bath. When solution was complete, the reaction was allowed to stand at room temperature. After two hours ice and water were added and the resultant oil was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 58 g of the title compound as an amorphous solid. The product, homogeneous by thin-layer chromatography using 1:1 ethyl acetate/Skellysolve B on silica gel, was employed for subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([CH2:10]Cl)=[CH:4][CH:3]=1.[C:12]1([C:18]([NH2:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:31]([C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1CCl
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Clc1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 6-chloro-2,3-bis-chloromethyl-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH+, 100%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[CH2:34][N:27]3[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:33]4[C:25]([C:21]4[NH:20][CH:24]=[CH:23][N:22]=4)=[N:26]3)[C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCN[C@@H](C)C2)c(F)cc1Cl
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. (S)-1-(4-Chloro-2-fluoro-5-methoxy-phenyl)-3-methylpiperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (29 mg): 1H NMR (CDCl3, 400 MHz) 8.79 (dd, 1H), 8.55 (dd, 1H), 7.27-7.21 (m, 3H), 7.07 (d, 1H), 6.43 (br. d, 1H), 5.46-5.37 (m, 2H), 4.83 (br. s, 0.3H), 4.51-4.48 (m, 0.6H), 4.28-4.21 (m, 0.6H), 3.86 (s, 0.9H), 3.85 (s, 2.1H), 3.79 (br. s, 0.3H), 3.67 (br. s, 0.3H), 3.33-3.21 (m, 2.5H), 2.95-2.93 (m, 0.9H), 2.83-2.76 (m, 1.6H), 1.48-1.40 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](C)(C)[C:10]([O:12]CC)=O)=O)[CH:2]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:9][C:10](=[O:12])[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)[CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccnc2)=NN1c1ccccc1
Yield: 93 %

Procedure:
A mixture of 1.5 g (6.8 mmol) of ethyl α-(3-pyridylcarbonyl)isobutyrate and 0.88 g (12 mmol) of phenyl hydrazine was dissolved in 50 ml of toluene, and the solution was dehydrated and heated under reflux in the presence of p-toluenesulfonic acid monohydrate (catalytic amount) for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2 (v/v)) to give 1.5 g of the object compound as white crystals (yield 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccccc1NC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of ethyl 2-aminobenzoate (3.0 g, 18 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (3.68 g, 1.6 mL, 18 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 3.32 g (65%) of the title compound as a white solid, mp 65°-66° C.: 1H NMR (DMSO-d6) δ11.08 (s, 1H), 8.25 (dd, J=7.6, J=0.8, 1H), 7.95 (dd, J=8.0, J=1.2, 1H), 7.63 (t, J=8.4, 1H), 7.25 (dt, J=7.6, J=1.2, 1H), 4.33 (q, J=7.2, 2H), 4.23 (s, 2H), 1.33 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ166.82, 165.02, 138.86, 133.95, 130.62, 123.93, 121.11, 118.23, 61.30, 30.40, 13.99; MS (EI, m/z) 287 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:11]1[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])=[O:10].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:11]1[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])(=[O:27])=[O:10]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(S(=O)c2ccc(Cl)cc2Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1cc([N+](=O)[O-])c(S(=O)(=O)c2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.7 %

Procedure:
To a solution of 1-[5-(2,4-dichlorophenyl)sulfinyl-4-nitro-2-thienyl]ethanone (100 mg, 0.275 mmol) in dichloromethane (2 mL), m-chloroperoxybenzoic acid (95 mg, 0.55 mmol) was added slowly at 0° C. The mixture was stirred at ambient temperature for 10 hours. Then the mixture was diluted with dichloromethane (10 mL) and washed with aqueous sodium bicarbonate solution (5 mL×3), then water (5 mL×2) and brine (5 mL). The organic phase was dried (Na2SO4), concentrated under vacuum and the residue was purified by chromatography to afford the title product (75 mg, 72% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.62 (1H, s), 8.32 (1H, d), 8.0 (1H, s), 7.87 (1H, m), 2.67 (3H, s). MS m/z: 378.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.P(Br)(Br)[Br:18].O>ClCCl>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: COCCOCCOc1ccc(CO)cc1
Solvent: O
Solvent: ClCCl
Product: COCCOCCOc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
To a solution of {4-[2-(2-methoxyethoxy)ethoxy]phenyl}methanol (Step 2, 500 mg, 2.21 mmol) in 10 mL dichloromethane was added dropwise phosphorous tribromide (210 μL, 2.21 mmol) at 0° C. After the addition was completed, stirring of the reaction mixture was continued for 1 h at the same temperature. Then, water was added with caution, and it was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to yield a crude product which was purified by MPLC (silica, cyclohexane/ethyl acetate 10:1) affording the title compound in pure form (530 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H), 6.88 (d, 2H), 4.50 (s, 2H), 4.13 (t, 2H), 3.85 (t, 2H), 3.71 (t, 2H), 3.58 (t, 2H), 3.40 (s, 3H); DCI(NH3)-MS m/z 306/308 (M+NH4)+; HPLC RT (Method I) 3.20 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1Cl
Reactant: O=C(C=Cc1ccc(Br)cc1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Temperature: 125 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
1-(4-Bromo-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (8.0 g, 24.3 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (5.7 g, 31.6 mmol) were added to acetic acid (116.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 8.5 g of the titled compound as a yellow liquid.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:37]([C@:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@](Cc1ccccc1)(C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
Boc-Tle-OH (4.8 g, 22.3 mmol) was dissolved in dichloromethane (50 mL), and EDCI (4.3 g, 44.6 mmol), DMAP (0.6 g, 4.46 mmol), DIPEA (16 mL, 89.2 mmol), and benzyl alcohol (5 mL, 44.6 mmol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (6.7 g, 99%).
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:30])[C:18]=2[CH:17]=1)=[O:15])=[O:6].[OH-].[Na+]>O>[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:30])[C:18]=2[CH:17]=1)=[O:15])([OH:6])=[O:4]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1C(=O)O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Yield: 71.8 %

Procedure:
To 80 ml of a methanol suspension containing 4.31 of N-(2'-methoxycarbonylphenyl)-5,6,7,8tetrahydro-9-oxo-xanthene-2-carboxylic acid amide obtained in Example 43 was added 10 ml of an aqueous solution containing 0.48 g of sodium hydroxide. The mixture was heated for 3 hours under refluxing and stirring conditions. The solvent was then removed by distillation to give a residue which was dissolved in hot water and filtered. The filtrate was acidified with concentrated hydrochloric acid to separate a yellowish white deposit. The deposit was collected by filtration, washed with water and then air-dried. Finally, the deposit was recrystallized from acetic acid to obtain 2.96 g (yield: 71.8%) of N-(2'-carboxyphenyl)-5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid amide.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:15]([CH3:45])([CH3:44])[O:16][Si:17]([CH3:43])([CH3:42])[O:18][Si:19]([CH3:41])([CH3:40])[O:20][Si:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)([CH3:23])[CH3:22])=[CH:6][CH:5]=1)([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:15]([CH3:44])([CH3:45])[O:16][Si:17]([CH3:43])([CH3:42])[O:18][Si:19]([CH3:40])([CH3:41])[O:20][Si:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)([CH3:22])[CH3:23])=[CH:6][CH:5]=1
Reactant: C[Si](C)(CCCCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Product: C[Si](C)(CCCCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
2.71 g of the above (2d) (3.73 mmol) and 15 mL of a 10 wt % Pd/C ethyl acetate solution (0.0150 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite, and then concentrated to obtain a colorless oily material of 1,7-bis(4-aminophenoxyhexyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3d) (2.47 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3d), and results are shown below.
Reaction SMILES: [C:1]([O:11][CH:12]([C:14]([C:17]([O:19]C)=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[Na+:22]>>[C:1]([O:11][CH:12]([C:14]([C:17]([O:19][Na:22])=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: [Na+]
Agent: [OH-]
Product: O=C(O[Na])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The procedure of Preparation 1 was followed except using 16.3 grams of C3F7OCHFCF2COOCH3 instead of the CF3O(CF2)3OCHFCF2COOCH3 and using 2 grams of sodium hydroxide (50 mmol) instead of potassium hydroxide.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C([O:6][C:7]([C:9]1[S:10][C:11]([S:14][CH2:15][CH3:16])=[N:12][N:13]=1)=O)C>>[CH2:1]([NH:3][C:7]([C:9]1[S:10][C:11]([S:14][CH2:15][CH3:16])=[N:12][N:13]=1)=[O:6])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1nnc(SCC)s1
Product: CCNC(=O)c1nnc(SCC)s1
Temperature: 4 °C

Procedure:
54 g of an aqueous 50% ethylamine solution were added to 43.7 g of the compound obtained in Example 8(c), that is ethylthio-1,3,4-thiadiazole-2-carboxylic acid ethyester. This caused the temperature to rise to 46° C. The solution was subsequently heated to boiling point for another 15 minutes. It was then cooled to 4° C. and reacted with 50 ml icewater. The precipitated compound was removed by suction.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(=O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Cc1nnc(-c2cccc(C(=O)O)n2)o1
Yield: 85.1 %

Procedure:
The title compound was prepared from 35 (4.5 mg, 0.010 mmol) following general procedure A. Flash chromatography (SiO2, 10% MeOH—CH2Cl2) afforded the title compound (3.4 mg, 85%) as a yellow solid: 1H NMR (DMSO-d6+0.1% TFA, 600 MHz) δ 8.29 (d, 1H, J=7.8 Hz), 8.17 (d, 1H, J=7.8 Hz), 8.08 (t, 1H, J=7.8 Hz), 7.57-7.55 (m, 4H), 7.36 (t, 2H, J=7.8 Hz), 7.29-7.25 (m, 2H), 4.02 (s, 4H); 13C NMR (DMSO-d6+0.1% TFA, 150 MHz) δ 202.1, 166.2, 164.7, 163.3, 150.0, 143.1, 142.2, 141.0, 139.9, 133.9, 131.1, 128.9, 128.0, 127.7, 127.5, 127.3, 126.7, 48.0, 39.8; HRMS-ESI-TOF m/z 400.1299 ([M+H]+, C23H17N3O4 requires 400.1292).