Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: NN
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Solvent: CCO
Product: NNc1cnc2cc(F)c(F)cc2n1
Reaction time: 8 h

Procedure:
The foregoing methodology was followed starting with 2-chloro-6,7-difluoroquinoxaline. This compound (4.00 g, 19.9 mmol) was dissolved in 100 ml of absolute EtOH. Hydrazine (1.4 ml, 44 mmol) was added, and the mixture heated at reflux for 21/2 hours. The mixture was cooled and allowed to stand overnight before collecting the resulting precipitate, yielding 3.80 g of an orange, solid 2-hydrazino-6,7-difluoroquinoxaline. This product (3.8 g, 19.4 mmol) was stirred in 30 ml triethylorthoformate and heated at reflux (100° C.) for 5 hours. The resulting product was cooled to room temperature, filtered and dried, yielding 2.63 g of 7,8-difluoro-1,2,4-triazolo[4,3-a]quinoxaline (13). The difluoro compound (13) (1.81 g 8.78 mmol) was added to glacial AcOH (25 ml) and treated with 80% monoperoxyphthalic acid Mg salt.6H2O (2.88 g, 4.66 mmol). The mixture was heated at 60°-70° C. overnight and initially went into solution, then a precipitate formed after 1-2 hours. This was allowed to cool, before pouring onto H2O. The precipitate was collected by filtration and air dried to yield 7,8-difluoro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (14).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>CCCCO>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (327 mg, 1.63 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (140 mg) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. Then the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% gradient CH3CN/water gradient; 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3ylcarbamate (105 mg, 47% yield) as a solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].[OH-].[Na+]>CS(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: OCc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.2 %

Procedure:
20.0g (93.5 mmoles) of 2-chloromethylquinoline hydrochloride, 11.6 g (93.5 mmoles) of 3-hydroxybenzyl alcohol and 7.48 g (186.42 mmoles) of powdered sodium hydroxide are combined in 56 ml of dimethylsulfoxide. After stirring room temperature for 24 hours the mixture is poured into ice-water and the resulting solid is collected and dried to give 25.6 g of 3-(2-quinolinylmethyloxy)benzyl alcohol.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])=[CH:22][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: Fc1ccc(CNC2CCCC2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CN(C(=S)Nc2ccccc2)C2CCCC2)cc1
Yield: 84 %

Procedure:
6.75 g (0.05 mol) of phenyl isothiocyanate were rapidly added dropwise to a solution of 9.65 g (0.05 mol) of N-4-fluorobenzyl-N-cyclopentylamine in 80 ml of toluene. The mixture was heated to the boil for 30 minutes, the solvent was distilled off in vacuo, and the residue was recrystallized from isopropanol. 13.8 g of N-4-fluorobenzyl-N-cyclopentyl-N'-phenylthiourea of melting point 135° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N=CC1C=CC=CC=1O)C1C=CC=CC=1>>[CH2:12]([N:19]=[CH:4][C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccccc1C=NCc1ccccc1
Product: COc1ccc(O)c(C=NCc2ccccc2)c1

Procedure:
This compound was prepared from 2.7 g of 2-hydroxy-5-methoxy-benzaldehyde, 2.3 mL of benzylamine and 0.03 g of p-toluenesulphonic acid using the procedure described for 64a. Yield: 4:3 g (oil).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:20])[NH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)[O-]
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Reaction time: 4 h

Procedure:
A mixture of 6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 1.9 parts of sodium acetate and 150 parts of acetic acid was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in 200 parts of a hydrochloric acid solution 10%. After stirring for 1 hour at reflux temperature, the whole was evaporated. The residue was taken up in water and treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone;
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:4][OH:5].CCN(CC)CC.P=PP.C1C[O:27][CH2:26]C1>>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C@@H:3]1[CH2:4][O:5][C:26](=[O:27])[NH:2]1
Reactant: N[C@@H](CO)c1ccc(F)cc1F
Reactant: C1CCOC1
Agent: Cl
Agent: P=PP
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred mixture of (R)-2-amino-2-(2,4-difluorophenyl)ethanol hydrochloride (0.58 g, 2.8 mmol) in THF (18 mL) was added Et3N (1.2 mL, 8.9 mmol). The reaction mixture was cooled in an ice bath under N2. A solution of triphosphene (0.33 g, 1.1 mmol) in THF (10 mL) was added. The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 1:1) to give (R)-4-(2,4-difluorophenyl)oxazolidin-2-one (0.50 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH2:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH:17][CH3:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 18 h

Procedure:
A stirred solution of 8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.02 mole) in dry dimethylformamide (50 ml.) is cooled in an ice bath under nitrogen and treated successively with a 57% mineral oil suspension of sodium hydride (0.84 g., 0.02 mole) and methyliodide (0.02 mole). The mixture is allowed to come slowly to ambient temperature and stand for 18 hours. It is then concentrated in vacuo. The residue is chromatographed on silica gel with methanol to give 8-chloro-1-[[(methylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17](I)=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>>[Cl:1][C:2]1[C:3]2[C:17]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of N-[4-chloro-5-iodo-7-(4-methoxy -3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (see Example 1) with ethynyl-trimethylsilane according to the General Procedure A. tR=7.48 min. 1H NMR (CDCl3) δ 8.18 (s, 2H), 7.38 (s, 1H), 5.49 (s, 2H), 3.74 (s, 3H), 2.24 (s, 6H), 1.35 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[C:33](OCC)(=[O:35])C.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[C:12]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:15]=1[CH:33]=[O:35]
Reactant: CCOC(C)=O
Reactant: CN(CCc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1)C(=O)Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (1.61 ml, 0.0173 mol) is added dropwise to 1.34 ml of N,N-dimethylformamide (DMF) while the reaction mixture is maintained between 10° to 20° C. with an external cooling bath. A solution of N-methyl-N-phenethyl-2-(3-benzyloxyphenyl)acetamide (3.73 g, 0.0144 mol) in DMF is added dropwise, the resulting mixture is heated at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture is poured into an ice/H2O mixture, ethyl acetate is added, followed by 7.3 g of sodium acetate. The resulting mixture is stirred for 1 hour. The layers are separated. The organic layer is washed with 10 ml of 1N aqueous HCl and brine; dried (MgSO4) and concentrated concentrated in vacuo. The residue obtained is purified by a flash column packed with silica gel and eluted with 5% ethyl acetate in CH2Cl2 to give N-methyl-N-phenethyl-2-(5-benzyloxy-2-formylphenyl)acetamide. NMR confirms this structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10](=[O:13])[N:9]2[CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:6][CH:7]=1
Reactant: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(Br)cc1
Yield: 58 %

Procedure:
Compound 11b (30.0 g, 125 mmol) was treated with SEMCl using the reaction conditions described in Example 10, Step C to obtain compound 11c as a white solid (30.0 g, 58% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2S: 370.1 (M+H). Found 370.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([CH3:17])([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:23])=[CH:20][CH:19]=3)[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)Cl)cc2)S1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)N3CCCC3)cc2)S1)c1ccc(F)cc1
Reaction time: 0.67 h

Procedure:
To a solution of 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoyl chloride (0.100 g, 0.26 mmol) in CH2Cl2 (1 mL) in a 0° C. bath was added pyrrolidine (Aldrich, 0.063 ml, 0.77 mmol). The mixture was gradually warmed to ambient temp. and stirred for 40 min. The reaction mixture was then added to water (5 mL), and the aqueous layer was extracted with CH2Cl2 three times. The combined organic phases were dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 426 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.Cl.[N:13]1([C@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:13]1([C@H:18]2[CH2:22][CH2:21][N:20]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:8])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: C1CCN([C@H]2CCNC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-fluorobenzoic acid (3.5 g, 24.98 mmol) in DMF is treated with (S)-1,3′-bipyrrolidine dihydrochloride (10.65 g, 49.96 mmol), triethylamine (12.64 g, 124.90 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (5.75 g, 28.98 mmol) and N-hydroxybenzotriazole (4.05 g, 29.98 mmol), stirred at room temperature for 16 h and concentrated in vacuo. The resultant residue is partioned between CH2Cl2 and H2O. The organic phase is separated, washed sequentially with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The concentrate is absorbed onto silica and purified by flash column chromatography (10% methanol in CH2Cl2) to give the title product, identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:28]N1C(=O)CCC1=O>ClCCl>[C:24]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[C:9]1[Cl:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)n1c(Cl)c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d]-pyrimidine (0.20 g), N-chlorosuccinimide (80 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (95:5) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 7-(tert-butyl)-6-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo-[2,3-d]pyrimidin-4-ylamine, m.p. 136.8-137.8° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=1)(=O)=O.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:25][CH2:24][CH2:23][NH:22][C:21](=[O:26])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:9][CH:10]=1)#[N:15]
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cn1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-cyanopyridin-2-yl)ethyl methanesulfonate (4.0 g, crude), tert-butyl(2-aminoethyl)carbamate (4.8 g, 30 mmol) and K2CO3 (3.2 g, 30 mmol) in 40 mL of DMF was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (100 mL×3). The combined EtOAc layer was washed with brine and concentrated. The residue was purified by silica gel column (DCM:MeOH=10:1) to afford the title compound.
Reaction SMILES: C(O[CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1)C.[Cl:26]C([SiH3])(Cl)Cl.C(OC(C)C)(C)C>C(#N)C>[Cl:26][CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1
Reactant: [SiH3]C(Cl)(Cl)Cl
Reactant: CCOCCNn1cc(C(=O)OCC)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cn(NCCCl)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(ethoxymethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (200 mg) in dry acetonitrile (2.0 ml) was added trichloromethylsilane (65.8 μl) under ice -cooling and the mixture was stirred for 30 minutes, and then for 10 minutes at room temperature. To the reaction mixture was added diisopropyl ether (10 ml), which was then stirred for 15 minutes at ambient temperature. The precipitate was collected by filtration and washed with diisopropyl ether and dried in vacuo over phosphorus pentaoxide to give ethyl 1-(chloromethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (145 mg).
Reaction SMILES: CN(C)CCN.[CH:7]1([O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.[C:28]([C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])(=O)[CH3:29]>CCO>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])=[C:31]([C:28](=[N:13][O:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:29])[CH:36]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NOC1CCCC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.1 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopentyloxy)phthalimide (345 mg, 1.50 mmol) in EtOH (5 mL, and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (302 mg, 1.0 mmol) in EtOH (2 mL), and the reaction stirred for 2.25 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-cyclopentyloxyiminoethyl)phenyl]trifluoromethanesulfonamide 163 (185 mg, 48%), as a pale yellow solid. 1H n.m.r. (400 MHz, CDCl3) δ 12.18, br s, 1H; 7.67, d, J=8.8 Hz, 1H, 7.49, d, J=2.4 Hz, 1H, 7.31, dd, J=2.4 and 8.8 Hz, 1H, 4.80, m, 1H, 2.30, s, 3H; 1.89, m, 4H, 1.74, m, 2H, 1.64, m, 2H. HRMS (M+) 384.0518. N-(Cyclopentyloxy)phthalimide was prepared by the procedure of Ishikawa, T.; Kamiyama, K.; Matsunaga, N.; Tawada, H.; lizawa, Y.; Okonogi, K.; Miyake, A. J. Antibiot., 2000, 53, 1071-1085.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C([O-])(O)=O.[Na+].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of indomethacin (6.388 g, 18 mmol) in anhydrous DMF (45 mL) were successively added NaHCO3 (1.4 g, 16.7 mmol) and tert-butylbromoacetate (2.95 g, 15 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then poured over ice-cold water, stirred, and the white solid obtained was filtered off, washed with water and dried. The product was recrystallized from EtOAc:hexane (1:4) to give the title compound (7.06 g, 88% yield) as a white soild. Mp 96–97° C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.6 (dd, J=9.0 and 2.4 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.77 (s, 2H), 2.37 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.1, 168.2, 166.6, 156.2, 139.2, 136.0, 133.8, 131.1 (2×C), 130.7, 130.5, 129.0 (2×C), 114.9, 112.1, 111.9, 101.1, 82.4, 61.5, 55.6, 29.7, 27.9, 13.4; LRMS (APIMS) m/z 472 (MH+).
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:15]=[O:16].[NH2:17]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:16]1[C:15]2[CH:1]=[CH:2][CH:3]=[CH:4][C:7]=2[CH2:8][CH2:9][NH:17]1.[C:10]1([OH:13])[CH:9]=[CH:8][C:7]([C:4]2[CH:5]=[CH:6][C:1]([OH:14])=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: C=O
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
27.9 g of 4,4′-biphenol and 48.6 g of aqueous formaldehyde (37%) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 80 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 27.9 g aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for 10 hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a pale orange solid. The pale orange solid was dissolved in ethyl ether and washed with 3N NaOH aqueous three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo to obtain pale orange 4,4′-biphenol dihydrobenzoxazine solid. m.p. 170° C. EA: Calcd.: C: 80.00%; H: 5.71%; N: 6.66%. Found: C: 80.30%; H: 5.73%; N: 6.56%.