Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[O:16]1[CH2:17][CH2:18][N:13]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OB(O)c1cccnc1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (100 mg) was reacted with 2-(piperidin-4-yl)ethanol following the protocol in General Procedure C. One half of the crude material was then used with pyridine-3-boronic acid in General Procedure A to give 42 mg of 143 following reversed phase HPLC purification. MS (Q1) 440 (M)+.
Reaction SMILES: [IH:1].[CH3:2][NH:3][C:4](=[N:7][CH3:8])SC.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>C(O)C>[IH:1].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:4]([NH:7][CH3:8])=[N:3][CH3:2])=[CH:12][CH:11]=1
Reactant: CN=C(NC)SC
Reactant: Cc1ccc(CN)cc1
Agent: I
Solvent: CCO
Product: CN=C(NC)NCc1ccc(C)cc1

Procedure:
A solution of N,N',S-trimethylisothiourea hydriodide, m.p. 208° -212° (9.84 g.) and p-methyl-benzylamine (4.84 g.) in ethanol (10 ml.) was refluxed for 31/2 hours, filtered, and refluxed for a further 21/2 hours. The solution was then concentrated, and the solid that separated was collected and crystallised from methanol-ethanol to give N-p-methylbenzyl-N', N"-dimethyl-guanidine hydriodide, m.p. 204° - 207°. Recrystallised from water, the m.p. rose to 209° - 212°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:16]=2)[NH:11][CH:10]=1.CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CN(C=O)C>[CH3:71][N:72]([CH3:81])[CH2:73][CH2:74][N:75]1[CH2:80][CH2:79][N:78]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[N:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:22])[CH2:77][CH2:76]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)nc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a mixture of 3-[7-(2-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (35 mg, 0.1 mmol), EDCI (77 mg, 0.40 mmol), HBTU (3.8 mg, 0.01 mmol) and diisopropylethylamine (175 μl, 1.0 mmol) in DMF (1 mL) was added 2-(dimethylamino)ethylpiperzine (55 μl, 0.3 mmol). The mixture was stirred at 70° C. for 5 hours before the solvents were removed. The resulting yellow oil was washed with water, dissolved in DMSO and purified on reverse phase HPLC to afford the title compound (8.6 mg, 12% over 2 steps) as yellow solid. MS: m/z 485.2 [MH+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14](=O)([O-])[O-:15].[Na+].[Na+]>C(OC)=O.CN(C=O)C>[OH:15][CH:14]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC=O
Product: COC(=O)C(=CO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of methyl phenylacetate (16.03g) in methyl formate (132ml) and dry DMF (100 ml) was added dropwise over 40 minutes to a stirred suspension of sodium hydride (5.14g) in dry DMF (200ml) at between 0° and 5° C. (effervescence and foaming). The resulting mixture was stirred at about -5° C. for 30 minutes, diluted with dry DMF (250ml), then allowed to warm and stir at room temperature for 3 hours. Ice and sodium carbonate were added to the mixture and it was washed with ether (x2), then acidified with concentrated hydrochloric acid and extracted with ether (x4). The extracts were washed with water (x3), treated with magnesium sulphate and charcoal, filtered and concentrated to give methyl 3-hydroxy-2-phenylpropenoate (13.56g, 71%) as a solid, m.p. 33.5°-35.5° C., which was used for the subsequent steps without further purification.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#N)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:17].[K+].Cl.C[OH:21]>O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:21])=[O:17])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(CC#N)ccc2s1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1nc2cc(CC(=O)O)ccc2s1
Temperature: 25 °C

Procedure:
The product from Step 5 (0.90 g, 0.004 mol) was dissolved in methanol (8 ml) and a solution of potassium hydroxide pellets (0.35 g, 0.006 mol) in water (2 ml) was added. The mixture was refluxed for 17 hours and was then cooled to room temperature. The mixture was acidified with concentrated hydrochloric acid to pH4 and the resultant solution was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to afford 2-tert-butyl-5-benzothiazolylacetic acid (0.5 g) as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].N1C=C[CH:18]=[CH:17][CH:16]=1.CC[O:23]CC>C(O)(C)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:23][CH:17]([CH3:18])[CH3:16])(=[O:11])=[O:10]
Reactant: c1ccncc1
Reactant: CCOCC
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CC(C)O
Product: CC(C)OS(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
A solution of 400 grams (g) of 2-trifluoromethylbenzenesulfonyl chloride in 600 milliliters (mL) of isopropanol was cooled in an ice bath and treated with a solution of 180 mL of pyridine in 200 mL of isopropanol at a rate to keep the internal temperature <10° C. The mixture was maintained at 0°-5° C. for 24 hours, then treated with 1 liter (L) of ether. The slurry was filtered and the solvent removed from the filtrate in vacuo. To the filtrate was added 800 mL of ether and the resulting mixture was washed with 500 mL portions of 5% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and then brine. The organic phase was dried through calcium sulfate and the solvent removed in vacuo to yield 306 g isopropyl 2-trifluoromethylbenzenesulfonate as an oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[CH:5]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O.Cl>[CH3:13][C:6]1[CH:5]=[C:4]([C:3]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: C#CC(=O)OCC
Reactant: Cc1cc(/C(Cl)=N/O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(C)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of (Z)—N-hydroxy-3-methyl-4-nitrobenzimidoyl chloride (1.0 equiv.), ethyl propiolate (2.0 equiv.) in toluene was dropwise added Et3N over a period of 30 min. at RT and continued stirring at RT for 15 min. The reaction mixture was then heated at 80° C. for 16 hours. Reaction mass was diluted with EtOAc and neutralized with dilute HCl. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 100% CHCl3, to provide the title compound as creamish crystals (65%); 1H NMR (300 MHz, DMSO-d6) δ: 1.31-1.36 (t, J=7.0 Hz, 3H), 2.56 (s, 3H), 4.35-4.42 (q, 2H), 7.99-8.02 (m, 2H), 8.08 (s, 1H), 8.11 (m, 1H); IR (KBr) 3124, 3091, 2995, 2908, 1727, 1612, 1588, 1520, 1443, 1344, 1285, 1140, 1015, 950, 873, 771 cm−1.
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)[Cl:2].[Cl:6][CH:7]([SiH2:9][C:10]1([Si](C)(C)C)[CH:14]=[CH:13][CH:12]=[CH:11]1)[Cl:8]>>[Cl-:2].[Cl-:6].[Cl-:2].[Cl:6][CH:7]([SiH2:9][C:10]1([Ti+3:1])[CH:14]=[CH:13][CH:12]=[CH:11]1)[Cl:8]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: C[Si](C)(C)C1([SiH2]C(Cl)Cl)C=CC=C1
Product: ClC(Cl)[SiH2]C1([Ti+3])C=CC=C1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a solution of 2.3 g (12.1 mmol) of titanium tetrachloride in dichlomethane, 3 g (12.1 mmol) of 1-dichloromethylsilyl-1-trimethylsilyl cyclopentadiene is added dropwise at 25° C. The reaction is stirred for two days at room temperature. The solvent is evaporated to dryness and the residue is extracted with hexane. When the hexane solution is concentrated, a yellow solid corresponding to (1-dichloromethylsilyl cyclopentadienyl) titanium trichloride is obtained (2 g, 6 mmol, yield: 50%). 1H-NMR (C6D6): 6.47 (m,2H), 5.49(m,2H), 0.70(s,3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH2:11]O)[C:9]#[N:10])(=O)=O.[C:13](=[O:26])([O:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])ON(C(C)(C)C)C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:13](=[O:26])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[O:19][N:20]([CH2:6][CH2:7][C:8]([C:9]#[N:10])=[CH2:11])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)NOC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC(C#N)CO
Agent: CCOC(=O)N(OC(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C#N)CCN(OC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-methylsulfonyloxy-2-(hydroxymethyl) butanenitrile (i.e. the product of Step E) (6.87 g, 0.039 mol), 1,1-dimethylethyl (ethoxycarbonyl)azanyl carbonate (7.65 g, 0.037 mol) (i.e. the product of Step F) and potassium carbonate (10.21 g, 0.074 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 20 h. The reaction mixture was poured onto iced water (100 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were washed with water (50 mL) and concentrated to a pale-tan oil (10.05 g). The oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel chromatography (0-100% gradient of ethyl acetate in petroleum ether as eluant). The appropriate fractions were combined to provide the title compound as a yellow oil (3.78 g).
Reaction SMILES: [OH-].[Na+].C(=[C:6]([CH:8]([CH2:10][OH:11])[OH:9])[OH:7])(C)C.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.C(Cl)(=O)C1C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH2:12]([O:11][CH2:10][CH:8]([OH:9])[CH2:6][OH:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=C(O)C(O)CO
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: OCC(O)COCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 46.1 %

Procedure:
The 50 ml of a 50% (w/v) sodium hydroxide solution are added 33 g (0.25 mole) of isopropylideneglycerol, 30.25 ml (0.25 mole) of benzyl chloride and 1.38 g (4 millimoles) of benzoyl chloride and 1.38 g (4 millimoles) of benzyltri-n-butylammonium. The mixture is stirred at 100° C. for 5 hours, then cooled to room temperature, diluted with 50 ml of water and extracted with ether. The extract is washed with water and then the solvent is distilled off under reduced pressure. To the residue is added 70 ml of 15% (w/v) sulfuric acid, and the mixture is stirred at 100° C. for 2.5 hours. After cooling, the unreacted material is removed by extraction with petroleum ether, the aqueous layer is neutralized and then extracted with ethyl acetate, and the extract is washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to give about 21 g of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[N:26]=[C:25]2[C:21]([N:22]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:23]=[N:24]2)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:18]2[N:26]=[C:25]3[C:21]([N:22]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[CH:23]=[N:24]3)=[CH:20][N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: Clc1ncc2c(ncn2C2CCCCO2)n1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ncc4c(ncn4C4CCCCO4)n3)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A 100-mL, round-bottom flask was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.170 g, 0.60 mmol), 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (0.200 g, 0.84 mmol), potassium carbonate (0.247 g, 1.79 mmol) and N,N-dimethylformamide (6 mL). The resulting mixture stirred overnight at 110° C. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether) to afford 1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 69%) as yellow oil. MS (ESI, pos. ion) m/z 486, 488 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:23]1([CH2:22][CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:10][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[N:8][C:7](=[O:17])[C:6]=3[CH:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCc1ccccc1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromo-3-phenylpropane (0.86 g, 4.3 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.48 g, 92%).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][C:7]([OH:9])=O)(=[NH:4])[NH2:3].S(Cl)([Cl:12])=O>>[ClH:12].[C:2]([CH2:5][CH2:6][C:7]([Cl:1])=[O:9])(=[NH:4])[NH2:3]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)CCC(=O)O
Agent: Cl
Product: N=C(N)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.52 g. (0.01 mole) of 3-amidinopropionic acid hydrochloride in 18 ml. of thionyl chloride is allowed to stir at room temperature overnight. The excess solvent-reactant is then removed under reduced pressure and the product is isolated as a yellow gum, which crystallizes on standing, 1.5 g.
Reaction SMILES: [CH2:1]([C:8]1S(=O)(=O)[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:22](#[N:27])/[CH:23]=[CH:24]/[C:25]#[N:26]>C(Cl)(Cl)Cl>[CH2:13]([C:10]1[CH:11]=[CH:12][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:24]([C:25]#[N:26])[C:23]=1[C:22]#[N:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCC1=CC=C(CCCCCCC)S1(=O)=O
Reactant: N#C/C=C/C#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CCCCCCC)c(C#N)c1C#N
Yield: 47.2 %

Procedure:
In a typical experiment 2,5-diheptylthiophene 1,1-dioxide (2 g, 6.4×10-3 mole) and fumaronitrile (0.5 g, 6.4×10-3 mole) in chloroform (5 ml) were heated in a sealed tube to 180° for 18 H. The contents of the tube were evaporated to dryness and chromatographed over silica (toluene as eluent) to afford 3,6-diheptylphthalonitrile (0.98 g, 47%) as a yellow solid. The material was recrystallised from ethanol to afford a colourless solid, mp 44°-46° C. 1H-nmr (CDCl3) shows S 7.52 (s, 2H); 2.85 (t, 4H); 1.0-1.9 (m, 20H); 0.90 (t, 6H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]CCC)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])(=[O:4])[CH2:2][CH3:3].[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29].[CH2:32](Cl)Cl>>[C:26]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:1]([CH:2]2[CH2:3][CH2:32]2)=[O:4])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCNc1ccccc1Oc1ccc(NC(=O)CC)c(C(=O)O)c1
Reactant: CCCC(=O)Cl
Reactant: ClCCl
Product: CCCC(=O)Nc1ccccc1Oc1ccc(NC(=O)C2CC2)c(C(=O)O)c1
Temperature: 110 °C
Yield: 31 %

Procedure:
A mixture of 5-(2-amino-phenoxy)-2-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (50.0 mg, 0.153 mmol, prepared according to EXAMPLE 2) and butyryl chloride (23.3 mg, 0.184 mmol) in CH2Cl2 (1.5 mL) was heated in a microwave oven at 110° C. for 10 minutes. The reaction mixture was allowed to reach room temperature and the solvent was removed by evaporation. The crude ester product was hydrolysed in methanol (2 mL) and 1M NaOH (1 mL) over night, acidified with 1M HCl and the product was isolated by filtration (18 mg, total yield: 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.CCN(C(C)C)C(C)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl.O>[CH2:38]([NH:40][C:41]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:42])[CH3:39]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: CCN=C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)NCC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of the product of Example 2 (20 mg, 0.05 mmol) in dichloromethane (2 mL) containing Hunig's base (10 μL, 0.07 mmol) was treated with ethyl isocyanate (6 μL, 0.07 mmol) and stirred at room temperature for 8 hours. The mixture was diluted with water and extracted with dichloromethane. The aqueous layer was separated and extracted with additional dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on a Gilson HPLC to give the title compound (12 mg, 50%) as a yellow solid; MS(ES) m/e 444 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17]([NH2:19])=[S:18].[H-].[Na+].[ClH:22]>CS(C)=O.C(OCC)(=O)C.O1CCOCC1>[ClH:22].[ClH:22].[NH2:19][C:17]1[S:18][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=3)=[CH:4][C:3]=2[N:16]=1
Reactant: COc1ccnc(-c2ccc(F)c(NC(N)=S)c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc3sc(N)nc3c2)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)-thiourea (0.104 g) in dimethyl sulfoxide (5 ml) was added a sodium hydride (60% dispersion in mineral oil ,15.4 mg), and the mixture was stirred at 100° C. for 5 hours. The mixture was diluted with ethyl acetate and washed with water three times and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g, 5% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried under reduced pressure to give 2-amino-5-(4-methoxypyridin-2-yl)benzothiazole dihydrochloride (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13]C1CCCCO1.O.[NH2:28][NH2:29].[C:30](Cl)(=[O:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[C:30]([N:28]1[C:11]([CH2:12][OH:13])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:29]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=C(C=C(COC1CCCCO1)c1ccccc1)c1cc(F)ccc1F
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1N=C(c2cc(F)ccc2F)CC1(CO)c1ccccc1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
To a solution of 5.8 g (16.2 mmol) 1-2 in 100 mL of pyridine was added 1.18 mL (24.3 mmol) hydrazine hydrate. The reaction was heated at 90° C. for 45 minutes, cooled to room temperature, and then to 0° C. Following the addition of 5.75 mL (80.9 mmol) of acetyl chloride, the cooling bath was removed and the reaction was stirred for 7 h. The reaction was then dumped into a separatory funnel with EtOAc and brine. The layers were separated, the organic phase was washed twice with 1M HCl, then with brine, dried over Na2SO4, and concentrated. The residue was twice dissolved in toluene and again concentrated to remove any remaining pyridine. The reside was dissolved in 100 mL of MeOH, 1.5 g (7.9 mmol) of p-toluenesulphonic acid was added, and the mixture was stirred for 2 h at room temperature. The reaction was then concentrated, the residue was dissolved in EtOAc, washed twice with a saturated solution of NaHCO3, then brine, dried over Na2CO3, and concentrated. The residue was triturated with Et2O and filtered to provide 1-3 as a white solid. Data for 1-3: LC-MS: rt=2.20 min, m/z=331 (M+1).
Reaction SMILES: B(Br)(Br)Br.ClCCl.ClCCl.C[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]2.O>ClCCl.CO.CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]2
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A 1.0M boron tribromide/dichloromethane solution (8.5 ml) was added at 0° C. to a dichloromethane solution (50 ml) of 6-methoxy-2H-isoquinolin-1-one (1.0 g). The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction was carried out with a dichloromethane/methanol mixed solvent (dichloromethane:methanol=10:1). The organic layer was dried with anhydrous sodium sulfate, followed by condensation to dryness under reduced pressure, thereby obtaining the title compound (0.4 g) as a pale yellow solid.