Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([NH:23][C:24]1[C:27]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:26](=[O:33])[C:25]=1[Cl:34])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:16])[CH2:10][CH2:9]2.ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:34][C:25]1[C:26](=[O:33])[C:27]2([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:24]=1[NH:23][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:16])[CH2:10][CH2:9]2)[C:3]([OH:35])=[O:2]
Reactant: COC(=O)C(Cc1ccc2c(c1)CCN2C(=O)c1ccncc1)NC1=C(Cl)C(=O)C12CCCCC2
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1ccncc1)NC1=C(Cl)C(=O)C12CCCCC2

Procedure:
The title compound was prepared from the compound of Example 13 in a similar manner to the compound of Example 2 as a white lyophilised powder (99%). δH NMR (d6 DMSO), 8.73 (2H, m), 7.78 (1H, dd, J 4.3 and 1.5 Hz), 7.61 (1H, m), 7.50 (2H, m), 7.18 (1H, s), 7.05 (1H, d, J 8.2 Hz), 4.58 (1H, m), 4.00 (2H, t, J 8.3 Hz), 3.23 (1H, dd, J 14.1 and 4.8 Hz), 3.06 (3H, m), 1.50 (10H, br m); m/z (ES+, 70 eV) 480 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>CN1C(=O)CCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:31])[CH:29]=[CH2:30])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCCNC4)ncn3)cc2)cc1
Solvent: CN1CCCC1=O
Product: C=CC(=O)N1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 0.069 mmol) in NMP (0.5 mL) at 0° C. was added acryloyl chloride (0.007 g, 0.083 mmol), and the reaction mixture was stirred at 0° C. for 5 min. The reaction mixture was quenched by adding 10% NaHCO3 solution and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with water (3 mL) and brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol: 98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1one (I-86) as an off white solid. 1H NMR (MeOD) δ ppm: 1.5-1.75 (m, 2H), 1.80-2.00 (m, 1H), 2.0-2.20 (m, 1H), 2.70-2.90 (m, 1H), 2.90-3.05 (m, 1H), 3.80-4.00 (m, 2H), 4.30-4.45 (m, 1H), 5.65 & 5.75 (d, J=10.8 Hz & d, J=10.8 Hz respectively, together 1H), 5.81 (d, J=10.8 Hz, 1H), 6.14 & 6.18 (d, J=17.2 Hz & d, J=19.2 Hz respectively, together 1H), 6.60-6.70 & 6.70-6.85 (m, together 1H), 6.97-7.00 (m, 4H), 7.04 (t, J=7.6 Hz, 1H), 7.32-7.38 (m, 4H), 8.04 & 8.07 (s, together 1H); LCMS: m/e 416.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 566.1 [(M+H)+]; mp 144° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[O:5]1)(=O)[CH3:2].[C:11]([NH:16][NH2:17])(=[O:15])[CH2:12][CH2:13][CH3:14].C(O)C>O>[CH3:10][C:6]1[O:5][CH:4]([C:1](=[N:17][NH:16][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH3:2])[CH2:9][CH2:8][CH:7]=1
Reactant: CC(=O)C1CCC=C(C)O1
Reactant: CCCC(=O)NN
Solvent: CCO
Solvent: O
Product: CCCC(=O)NN=C(C)C1CCC=C(C)O1
Yield: 11.6 %

Procedure:
A mixture of 5.0 gm (0.0356 mole) of 2-acetyl-6-methyl-2,3-dihydropyran, 3.64 gm (0.0356 mole) of n-butyric acid hydrazide and 100 ml of ethanol is refluxed 24 hr. The mixture is diluted with water to the cloud point and chilled. The product is collected, washed with water and dried to give 0.93 gm (12%) of the title compound having a melting point of 72.8° C.
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][N+:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:18])[CH:11]=[CH:10][CH:9]=1.N>O.[Ni]>[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:18])[CH2:11][CH2:10][CH2:9]1
Reactant: C[n+]1cccc2cccc(O)c21
Agent: [Ni]
Agent: COS(=O)(=O)[O-]
Agent: N
Solvent: O
Product: CN1CCCc2cccc(O)c21

Procedure:
One introduces into a steel autoclave 54.2 g of N-methyl-8-hydroxyquinolinium methylsulfate (i.e. 0.2 mole) in 100 ml of water and 5 g of activated Raney nickel. The hydrogenation is effected under a hydrogen pressure of from 70 to 80 kg/cm2, at a temperature of 80°C. After cooling, one filters off the catalyst and one neutralizes with an ammonia solution. One dries the crystallized product that is formed and one recrystallizes it in methanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[C:22]([O:24][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccccc1
Reactant: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)OCc1ccccc1
Reaction time: 120 h

Procedure:
To a mixture of 0.90 g 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid, 10 ml dichloromethane, 0.24 ml benzyl alcohol and 30 mg dimethylaminopyridine, was added with stirring 0.46 g dicyclohexylcarbodiimide at room temperature, and stirring was continued for five days. The urea which separated out was filtered off, and the filtrate was washed with 0.1N caustic soda solution and then with water. After dehydration, the solvents were distilled off, and the residue was purified by silical gel column chromatography, affording 1.05 g of benzyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:22])[CH2:4][C:5]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.OO.C(OCC)(=[O:27])C.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH3:22])[CH2:4][C:5]1[CH2:11][CH2:10][S:9](=[O:27])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)CC1=C(c2cccnc2)c2ccccc2SCC1
Reactant: CCOC(C)=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CC1=C(c2cccnc2)c2ccccc2S(=O)CC1
Reaction time: 24 h

Procedure:
0.5 g of dimethyl-(5-pyridin-3-yl-2,3-dihydro-benzo[b]thiepin-4-ylmethyl)-amine hydrochloride was dissolved in 2.5 ml of glacial acetic acid; 0.29 ml of 35% hydrogen peroxide solution was added dropwise at room temperature, with stirring, and stirring was continued for 24 hours. The reaction mixture was covered with a layer of ethyl acetate, while cooling with ice, rendered alkaline with 32% sodium hydroxide solution and extracted three times with ethyl acetate; the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. 0.35 g of crude product was obtained and was purified by means of preparative HPLC (Hypercarb 5 μm 120×4 mm, 0.5 ml/min., acetonitrile/water (v/v=70:30+0.1% diethylamine). After filtration through a MF-Millipore-MCE membrane (mixed cellulose esters; 0.45 μm), 0.102 g of dimethyl-(1-oxo-5-pyridin-3-yl-2,3-dihydro-1H-1λ4-benzo[b]thiepin-4-ylmethyl)-amine was obtained and was dissolved in 3 ml of 2-acetone p.a. and converted into the corresponding hydrochloride with about 0.003 ml of water and about 0.041 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was dried in vacuo (about 50 mbar) (yield 0.1 g).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[C:11]2=[N:10][N:9]=1)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=3)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([CH2:6][CH2:7][C:8]1[N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[C:11]2=[N:10][N:9]=1)=[CH:17][C:16]([C:22]([F:24])([F:25])[F:23])=[CH:15][CH:14]=3)([OH:5])=[O:3]
Reactant: CCOC(=O)CCc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
A suspension of 1-(2-ethoxycarbonylethyl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (177 mg, 0.5 mmol) in 6 ml of 1N sodium hydroxide was stirred at room temperature for 150 min. The solution was cooled in an ice bath and acidified with 4M hydrochloric acid to pH 1. The precipitate was isolated by filtration, washed with water, ethanol and ether to give 131 mg (80%) of the title compound. M.p. 333° C. (DSC).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,5-dibromopentane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca 100 mL) to remove the excess of 1,5-dibromopentane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 1.01 g (609%). 1H-NMR (400 MHz, d6-DMSO) δ=1.40-1.52 (m, 2H), 1.75-1.85 (m, 2H), 3.52 (t, J=6.6 Hz, 2H), 3.78-3.89 (m, 2H), 6.64 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 334.1 (100, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][CH:27]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[C:13]([CH3:23])=[C:12]1[CH3:24])[CH3:5].[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH:41][C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH2:10][C:9]2[CH:8]=[C:7]([CH:27]=[CH:26][CH:25]=2)[O:6][C@@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:28])[C:12]([CH3:24])=[C:13]3[CH3:23])=[O:22])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol, 1 equiv) in DCM (2 mL) was added (S)-1-(3-isopropoxyphenyl)ethanamine (34 mg, 0.16 mmol, 1.2 equiv), DIEA (70 μL, 0.39 mmol, 3 equiv) and HATU (50 mg, 0.13 mmol, 1 equiv). The reaction mixture was stirred 2 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt and washed with a 0.5N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->50%) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12](I)=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.O.[Cu](I)I.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>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:25]#[C:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 28.5 %

Procedure:
Nitrogen was bubbled through a mixture of N-[3-(3-fluorophenyl)-4-iodo-1H-pyrazol-5-yl]acetamide (10.8 g, 44 mmol), phenyl acetylene (12.5 g, 123 mmol), triethylamine (100 mL) and DMF (40 mL) for 15 min. Copper iodide (840 mg, 4.42 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.5 g, 2.1 mmol) were added and the reaction mixture was stirred at 90° C. under nitrogen for 6 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 1:0 to 0:1) yielding the title compound as a solid (4 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](O)=[O:37])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:36](=[O:37])[CH2:35][C:27]4[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=4)[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)NC2C=CC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (47 mg, 0.15 mmol) in CH2Cl2 (2.5 mL) was added 3,4,5-trimethoxy phenyl acetic acid (45 mg, 0.20 mmol), Et3N (0.053 mL, 0.38 mmol) and EDCI (38 mg, 0.20 mmol) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (23 mg, 29%). Mass Spectrum (FIA) (m/z) 522.2 (M−1). 1H NMR (CDCl3): δ 7.43 (d, 1H); 7.37 (m, 2H); 6.42 (s, 2H); 5.88 (m, 2H); 5.18 (m, 1H); 3.78 (s, 9H); 3.47 (s, 2H); 2.90 (m, 2H); 1.98 (m, 2H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.O[C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]2[S:27][CH2:26][CH2:25][N:20]2[C:21](=[O:24])[C:22]=1[CH3:23].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[CH3:23][C:22]1[C:21](=[O:24])[N:20]2[CH2:25][CH2:26][S:27][C:19]2=[C:18]([N+:28]([O-:30])=[O:29])[C:17]=1[O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCS2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCS2
Reaction time: 2 h
Yield: 22.8 %

Procedure:
Triflic anhydride (3.4 g, 12.06 mmol) was added to a stirred solution of 7-hydroxy-6-methyl-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (2.5 g, 10.96 mmol) and TEA (2.3 mL, 16.44 mmol) in DCM (20 mL) at −70° C. The resulting mixture was stirred at −70° C. to −50° C. for 2 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was diluted DCM and quenched with bicarbonate solution. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 0.9 g of the product (38% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])=[O:6])[CH3:2].C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])=[CH:9][C:8]=1[OH:14])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of (2,4-Dihydroxy-phenyl)-oxo-acetic acid ethyl ester (from step 1, 2.71 g, 12.9 mmol, 1 eq) in anhydrous DCM (40 mL) solution was added triethylamine (1.97 mL, 14.2 mmol, 1.1 eq), followed by addition of tert-butyldimethylchlorosilane (1.89 g, 14.2 mmol, 1.1 eq)/DCM (10 mL) solution dropwise at 0° C. under argon. The reaction mixture was stirred at 0° C. for 5 min. Water (30 mL) was added to the reaction mixture to quench the reaction. The organic layer was washed with water (2×30 mL), dried over Na2SO4, filtrated, and concentrated under reduced pressure to afford a light yellow solid (4.1 g, contains 40% mono-substituted product) as crude product. This material was used in step 3 without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40])=[O:4].O1CCCC1.[OH-].[K+]>CO>[CH3:47][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 2 h
Yield: 20.2 %

Procedure:
1-Methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (0.092 mmol) was dissolved in methanol (0.25 mL) and tetrahydrofuran (0.25 mL) and 50% w/v aqueous potassium hydroxide (0.1 mL) was added at 0° C. After 2 hours, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was redissolved in tetrahydrofuran and the insoluble salts were removed by filtration. The crude material was purified by preparative HPLC to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (9.2 mg, 20.2%, 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.C(Cl)Cl.C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[NH:8][CH2:9][CH2:10][N:11]([S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:12]1
Reactant: COc1cccc(CC2CNCCN2)c1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(3-methoxybenzyl)piperazine (128 mg, 0.62 mmol), 5 mL of CH2Cl2, triethylamine (0.129 mL, 0.93 mmol) and 2-thiophenesulfonyl chloride (0.113 mL, 0.62 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was stirred at 0° C. for 1 h and then diluted with aqueous saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 3-(3-methoxybenzyl)-1-(thiophen-2-ylsulfonyl)piperazine as a colorless oil (162 mg).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccc(F)cc3)c(=O)n12
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3ccc(F)cc3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.062 g, 0.19 mmol) in tetrahydrofuran (0.6 mL) and water (0.14 mL,) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.226 mL, 0.226 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and then the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C15H15FN3OS (M+H)+: m/z=304.1. Found: 304.1.