Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=O)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=O)[C:4]=2[CH:3]=1.[B].CSC.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)c2ccccc12
Agent: [B]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Clc1ccc2c(c1)Cc1ccccc1CN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
To a mixture of 7.28 g of 2-chloro-5H-dibenz[b,e]azepine-6,11-dione in 25 ml of anhydrous tetrahydrofuran, under argon, is added dropwise 8.5 ml of (10M) boron-dimethyl sulfide. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is heated at reflux for 3 hours and cooled to room temperature. While stirring, 25 ml of methyl alcohol is carefully added, followed by 100 ml of 2N NaOH. The reaction mixture is heated at reflux for 24 hours and the solid collected. The solid is dissolved in methylene chloride and washed with 2N citric acid, water and dried (Na2SO4). The volatiles are evaporated in vacuo to give 4.16 g of a residue which is crystallized from ethyl acetate-hexane to give 2.05 g of the desired product as a crystalline solid, m.p. 137°-141° C.
Reaction SMILES: C([O:5][C:6]([C:8](NC(=O)OC(C)(C)C)=[CH:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.[O:27]1CCNC1>C1COCC1>[C:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH:9]=[C:8]([OH:27])[C:6]([OH:5])=[O:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1COCN1
Reactant: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Temperature: -40 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of Ethyl 5-(tert-butyl)oxazole-4-carboxylate 2 (20 g, 101 mmol) in anhydrous THF (250 mL) was added LiAl (3.84 g, 101 mmol, Kanto Chemical, Tokyo, Japan, Cat. No. 24115-35) portionwise under argon atmosphere at −60° C., and the bath temperature was gradually increased up to −40° C. with stirring for 2 h. (In case that the temperature was more than −40° C., the reduction of the oxazole ring (oxazolidine formation) predominantly proceeded). After the reaction mixture was quenched with saturated NH4Cl aq (50 ml) at −60° C. (Please avoid rapid elevation of temperature. Some impurity increased.), AcOEt (250 ml) was-added and stirred for a few minutes, and the resulting precipitate was removed by celite filtration (Celite-535, Nacalai Tesque, Kyoto, Japan, Cat. No. 07509-05). The filtrate was washed with water (×2), 10% citric acid (×3, a byproduct, oxazolidine, can be removed by this separation) and saturated NaCl (×3), dried over anhydrous Na2SO4, and concentrated in vacuo to give an oil of corresponding oxazole alcohol 3 (10.6 g, 67%). Rf 0.50 (CHCl3:MeOH=10:0.5), 1H NMR (300 MHz CDCl3) δ 7.71 (s, 1H), 4.66 (s, 2H), 1.36 (s, 9H); HRMS(EI): m/z 155.0852 (M+) (Calcd for C8H13NO2: 155.0854). This oil was used to the next oxidation without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:9]1=[O:23].C(C1C=C(C=CC=1)N)#N.Cl.N[NH:45][C:46]([NH2:48])=[O:47].CN1CCOCC1>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:31])=[O:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:48][C:46](=[O:47])[NH:45][N:19]=3)[CH:16]=2)[C:9]1=[O:23]
Reactant: NNC(N)=O
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3cccc(C#N)c3)C2=O)c(F)c1
Agent: Cl
Agent: N#Cc1cccc(N)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3cccc(-c4n[nH]c(=O)[nH]4)c3)C2=O)c(F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A sample of 3-[1-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-2-oxo-piperidin-3-ylamino]-benzonitrile, prepared from the compound of Ex. 1, part A and 3-cyanoaniline according to the procedure of Ex. 1, Part B, was suspended in a 2:1 mixture of anhydrous MeOH and chloroform and cooled in a 0° C. ice-bath. HCl gas was then bubbled in the mixture for 30 minutes resulting in a clear solution. The reaction vessel was sealed and stored at 0° C. for 18 hours. The mixture was concentrated in vacuo and dried. The resulting residue was suspended in 1,4-dioxane. Semicarbazide hydrochloride (1.7 eq) was then added, followed by N-methylmorpholine (7.2 eq). The mixture was refluxed for 48 hours. The precipitate was filtered and washed with 1,4-dioxane, water, and ether. The solid was pumped dry to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 11.87 (s, 1H), 11.56 (s, 1H), 8.11(d, J=8.1 Hz, 1H), 7.75 (m, 2H), 7.47 (m, 2H), 7.37 (d, J=11.0 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.08 (br m, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.78 (br d, J=9.5 Hz, 1H), 4.28 (m, 1H), 3.73 (t, J=6.2 Hz, 2H), 2.90 (s, 3H), 2.30 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H); MS ESI (M+H) 522.4.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(#N)C>[C:1]([CH:3]([C:19](=[O:22])[CH2:20][CH3:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)C(=O)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A solution of ethyl cyanoacetate (17.0 g, 150 mmol), magnesium chloride (14.4 g, 151 mmol) and triethylamine (42 mL, 301 mmol) in acetonitrile (150 mL) was stirred at 0° C. for 15 minutes. To the solution, propionyl chloride (13.8 g, 150 mmol) was added dropwise over 15 minutes at the same temperature, and subsequently the solution was allowed to warm to room temperature and stirred for 24 hours. After addition of 30% hydrochloric acid (100 mL), the organic matter was extracted with diethylether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude ethyl 2-cyano-3-oxopentanoate (24.6 g, 97% yield). The compound (25.4 g, 150 mmol) was dissolved in a mixed solvent of dimethylsulfoxide (50 mL) and water (5 mL), and the solution was stirred at 120° C. for 1.5 hours. The solution was allowed to cool to room temperature and poured into saturated brine, and the organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure to give the title compound (14.6 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(CBr)nc2c1
Reaction time: 24 h

Procedure:
A solution of the benzoxazol (1.3 ) (Step 2) in CCl4 (15 mL) was treated with N-bromo-succinimide (NBS) (1.5 ) and benzoyl peroxide (38 mg) at reflux using a U.V. lamp for 24 hours. Filtration, evaporation, and flash chromatography of the residue using 1:1 hexane/toluene afforded the title compound which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](O)=[O:26])[C:20]2=[O:28])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH2:4][C:5](=[O:11])[NH:6]4)=[O:26])[C:20]2=[O:28])=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1CC(=O)N2
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1Cc2c(cccc2NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)N1

Procedure:
4-aminooxindole (80 mg, 0.54 mmol) was made to react to 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (125.5 mg, 0.54 mmol) in the presence of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 250 mg, 0.78 mmol) and triethylamine (TEA, 0.23 mL, 1.62 mmol) in a mixture of dry DMF and acetonitrile (1:3, 6 mL) under rt for 14 hours. Resultant solid was collected by filter, washed by methanol, water and ether, and dried to give 1-(4-fluorophenyl)-2-oxo-N-(2-oxoindolin-4-yl)-1,2-dihydropyridine-3-carboxamide: YD: 56%; mp: 293-295° C. 1H-NMR (400 MHz, DMSO-d6): 11.77 (s, 1H), 10.41 (s, 1H), 8.58 (dd, J=7.6, 2 Hz, 1H), 8.10 (dd, J=6.6, 2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.59 (m, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.17 (dd, J=8, 7.6 Hz, 1H), 6.71 (dd, 7.6, 6.6 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 3.36 (s, 2H). (C20H14N3O3F. 0.3; H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:30][CH2:31][CH2:32][CH2:33]O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:33][CH2:32][CH2:31][I:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCCI
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) in tetrahydrofuran (100 mL) at 0° C. was added triphenylphosphine (22.6 g, 86.33 mmol), 3-iodopropanol (16.73 g, 89.93 mmol), and diethylazodicarboxylate (14.3 mL, 86.33 mmol). The resulting mixture was stirred at 25° C. overnight. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried and concentrated. The residue was triturated with 8:1 ether/ethyl acetate to induce the precipitation of 22 g of triphenylphosphine oxide which was separated by filtration. The filtrate was preabsorbed onto silica gel and flash-chromatographed (5:1 hexane/ethyl acetate) to afford 17.5 g (79%) of white solid product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:26])([F:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[N:6][CH:7]=1.BrC(F)([F:34])C(OCC)=O.BrC1C=CC(F)=CN=1>CS(C)=O.[Cu]>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:9]([OH:16])([CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1)[C:8]([F:26])([F:25])[C:5]1[CH:4]=[CH:3][C:2]([F:34])=[CH:7][N:6]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Agent: [Cu]
Agent: Fc1ccc(Br)nc1
Solvent: CS(C)=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 10 was prepared in a similar manner to compound 1. To a stirred solution of ethyl 2-bromo-2,2-difluoroacetate (2.18 mL, 17.0 mmol) in DMSO (18 mL) was added copper powder (2.16 g, 34.0 mmol) at RT under N2 atmosphere. After being stirred for 2 h at RT, 2-bromo-5-fluoropyridine (1.50 g, 8.52 mmol) was then added, and stirring was continued for 3 h at RT. The progress of the reaction was monitored by TLC. The reaction was quenched with aqueous NH4Cl and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product mixture. Purification by column chromatography (eluting with EtOAc/hexane) afforded the ester (1.40 g, 6.3 mmol, 77%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H), 7.78 (dd, J=9.0, 4.0 Hz, 1H), 7.60-7.51 (m, 1H), 4.42-4.32 (m, 2H), 1.39-1.31 (m, 3H). MS (ESI): m/z 220 [M++1].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:19])[CH:7]=1>OS(O)(=O)=O>[F:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:19])[CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccc(F)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)c1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
HNO3 (6.92 g, 71.4 mmol) was added dropwise to a suspension of ethyl 2-(4-fluoro-2-methylphenyl)-2-oxoacetate (15 g, 71.4 mmol) in conc. H2SO4 (50 mL) at ° C. After complete addition the resulting mixture was stirred at 0° C. for 30 min. The mixture was poured into ice water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)-2-oxoacetate (15 g, 83% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J=7.2 Hz, 1 H), 7.24 (d, J=7.2 Hz, 1 H), 4.47 (q, J=7.2 Hz, 2 H), 2.67 (s, 3 H), 1.43 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:10]=3[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(Cl)cc1)CC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A solution of 2-(4-chlorophenyl)cyclopentanone (7.80 g, 40.1 mmol) and carbonisocyanatidic chloride (7.61 g, 72.1 mmol) was stirred at 58° C. in a high-pressure vessel for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for an additional 2 h. After cooling to rt, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (5.4 g, 20.48 mmol, 51.1% yield). LC-MS (M+H)+=264.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.32 (2H, d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz), 4.15-4.25 (1H, m), 2.56-2.93 (4H, m).
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[NH:25])=[NH:22])=[NH:12])=[NH:9])=[CH:5][CH:4]=[C:3]([Cl:34])[CH:2]=1.[N+]([O-])([O-])=O.[Ag+:39].[Ag+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CO>[Ag+3:39].[CH:28]1[C:27]([NH:26][C:24]([NH:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C:8]([NH:7][C:6]2[CH:1]=[CH:2][C:3]([Cl:34])=[CH:4][CH:5]=2)=[NH:9])=[NH:12])=[NH:22])=[NH:25])=[CH:32][CH:31]=[C:30]([Cl:33])[CH:29]=1
Reactant: [Ag+]
Agent: N=C(NCCCCCCNC(=N)NC(=N)Nc1ccc(Cl)cc1)NC(=N)Nc1ccc(Cl)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: [Ag+3]

Procedure:
According to a method described in WO2007/000590, a microcrystalline silver (III)/chlorhexidine complex was prepared. 0.49 mmol of chlorhexidine (1,1′-hexamethylenebis[5-p-chlorphenyl]biguanide) (0.25 g) was dissolved in 25 ml warm methanol and stirred to prepare a chlorhexidine solution. To the chlorhexidine solution was added drop wise an aqueous solution (1.25 ml) containing 0.05 mmol of silver nitrate (0.085 g). To the reaction mixture of silver (I) and chlorhexidine was added drop wise an aqueous solution (1.25 ml) containing 0.99 mmol of sodium persulphate (0.235 g) as oxidizing agent. After the addition of an oxidizing agent, the reaction mixture was warmed until an orange-brown is fully developed. The precipitate was filtered under vacuum and washed three times with warm methanol to yield a microcrystalline silver (III)/chlorhexidine complex.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27]C2CC2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:27][C:4]1[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:38][CH2:4][CH2:5][CH2:10][CH3:9])=[O:37])=[CH:34][CH:33]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(Nc2nc(N)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 122.2 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (245 mg, 0.557 mmol), 4-aminobenzoic acid (150 mg, 1.09 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in nBuOH (4 mL) was stirred at 135° C. for 24 h. It was concentrated in vacuo. The residue was purified by HPLC to give butyl 4-(4-amino-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzoate (137 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=2)[CH3:9])=[CH:4][CH:3]=1.Br[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23].[Mg].C1C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl.C(O)(=O)C.O>[CH3:23][C:22]1[CH:21]=[CH:20][S:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C1=NC(C)(C)CO1)c1ccc(I)cc1
Reactant: Cc1ccsc1Br
Agent: Cl[Pd]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccsc1-c1ccc(C(C)C2=NC(C)(C)CO2)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 8.0 g of 2-[1-(4-iodophenyl)ethyl]-4,4-dimethyl-2-oxazoline in 24 ml of anhydrous tetrahydrofuran was added 0.080 g of palladium chloride and the mixture was kept at 60° to 65° C. On the other hand, a Grignard reagent was prepared from 5.2 g of 2-bromo-3-methylthiophene, 0.8 g of magnesium turnings and 15 ml of anhydrous tetrahydrofuran. The Grignard reagent was added dropwise to the above mixture over a period of 30 minutes, while maintaining the temperature at 60° to 65° C. After the addition, the mixture was stirred at the same temperature for one hour to complete the reaction. After removal of the solvent by distillation under reduced pressure, to the residual reaction mixture were added 50 ml of benzene, 50 ml of water and 5 ml of glacial acetic acid, and the mixture was shaken thoroughly. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 6.8 g (93.3% yield) of oily 2-[1-[4-(3-methyl-2-thienyl)phenyl]ethyl]-4,4-dimethyl-2-oxazoline.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:29]2[CH:30]=[C:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH:33][C:28]=2[O:27][CH2:26]1>O1CCCC1>[O:27]1[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:30][C:29]=2[CH2:25][CH2:26]1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,3-dihydrobenzo[b]furan-5-isocyanate (197 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 268 mg (81.0%) of the desired product as a solid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([C:17]45[CH2:26][CH:21]6[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]6)[CH2:18]4)[CH2:24]5)[C:14]([O:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)=[CH:13][C:12]=3[O:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd].CN(C)C=O>[C:1]12([C:11]3[CH:16]=[C:15]([C:17]45[CH2:18][CH:19]6[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]6)[CH2:26]4)[CH2:24]5)[C:14]([O:27][C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=4)=[CH:13][C:12]=3[O:37][C:38]3[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])cc3)c(C34CC5CC(CC(C5)C3)C4)cc2C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cc(Oc3ccc(N)cc3)c(C34CC5CC(CC(C5)C3)C4)cc2C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Next, in a 300 mL recovery flask, 29.1 g of the obtained 4,6-di(1-adamantyl)-1,3-bis(4-nitro-phenoxy)benzene (46.8 mmol), 1.49 g of 10% palladium-activated carbon (1.40 mmol), 273 mL of N,N-dimethylformamide and a stirrer were charged and agitated at 25° C. for 24 hours under a hydrogen atmosphere. A reaction solution was filtered and then added to 1 L of ion-exchange water. Solid precipitate was collected by filtration, then agitated in 1 L of ion-exchange water for another one hour and dried under reduced pressure, thus obtaining 22.3 g of 4,6-di(1-adamantyl)-1,3-bis(4-amino-phenoxy)benzene (39.7 mmol; the yield was 84.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][CH2:66][C:67]([NH:69][C@@H:70]([C:78]([OH:80])=[O:79])[CH2:71][CH:72]1[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]1)=[O:68].[BH4-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:65][CH2:66][C:67]([NH:69][C@@H:70]([C:78]([OH:80])=[O:79])[CH2:71][CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)=[O:68])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Reaction time: 22 h
Yield: 31.9 %

Procedure:
To a solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.039 mmol) and NMM (0.025 ml, 0.227 mmol) in DMF (3 ml) at RT was added TBTU (0.025 g, 0.078 mmol). The reaction mixture was stirred for 90 min after which glycyl-3-cyclohexyl-D-alanine (0.010 g, 0.044 mmol) was added. The mixture was stirred for 22 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (1 ml) and then NaBH4 (0.016 g, 0.423 mmol) was added. After 10 min the reaction was quenched by the addition of a 0.1M ammonium acetate buffer (2 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.009 g, 32% yield).