Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a3) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].N[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1.Cl.N([O-])=[O:15].[Na+]>O.[Cu]Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([S:1]([Cl:4])(=[O:2])=[O:15])=[CH:11][N:10]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Cl)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of SO2 was prepared by adding thionyl chloride (24.2 mL) into stirring water (144 mL) containing copper (I) chloride (87.0 mg). The solution was then stirred at room temperature overnight. 5-Amino-2-chloropyridine (10.0 g, 77.8 mmol) was added into stirring conc. aq. HCl (80 mL) portionwise. The mixture was stirred until all solid dissolved and was then cooled to −5° C. Into the mixture was added dropwise a solution of sodium nitrite (5.9 g, 85.6 mmol) dissolved in 24 mL of water while the temperature was kept between −5° C. and 0° C. The resulting mixture was stirred for 30 minutes after the completion of the addition and then added dropwise into the aqueous solution of SO2. The temperature was kept below 0° C. during the addition. After the addition the mixture was stirred for 1 h below 0° C. and then filtered. The cake was washed with ice-cold water, dissolved in CH2Cl2, dried over Na2SO4 and concentrated to give 2-chloropyridine-5-sulfonyl chloride as a grey solid (13.6 g, 82%). 1H NMR (500 MHz, CDCl3): δ 9.04 (1H, d, J=2.4 Hz), 8.27 (1H, dd, J=8.5 Hz, J=2.6 Hz), 7.62 (1H, dd, J=8.5 Hz, J=0.4 Hz).
Reaction SMILES: C(O)[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5]CC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:21]1([CH3:39])[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][CH:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:2]([O:38][CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:31][O:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH3:39])=[CH:26][CH:25]=1)(=[O:28])=[O:29])(=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(O)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCC(COS(=O)(=O)c1ccc(C)cc1)OC(=O)CCC

Procedure:
Using 1,2-heptanediol, pyridine and p-toluenesulfonyl chloride, (RS)-1-p-toluenesulfonyloxy-2-heptanol 2c ##STR26## was prepared in the same manner as Example 1 of Production.
Reaction SMILES: [Fe:1].[C:2]([OH:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].[F-].[NH4+].C([O-])=O.[NH4+]>O>[C:2]([O-:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].[Fe+2:1].[C:2]([O-:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCCC(=O)O
Reactant: [Fe]
Agent: O=C[O-]
Agent: [F-]
Agent: [NH4+]
Solvent: O
Product: CC(C)CCCCC(=O)[O-]
Product: [Fe+2]
Temperature: 95 °C

Procedure:
A mixture of 46 grams (0.806 mole) of powdered iron (97.8% Fe) (100% through a 100 mesh screen), 292 grams (2.014 moles) of isooctanoic acid (acid number, 387), a catalyst solution prepared by dissolving 10 grams of ammonium fluoride and 5 grams of ammonium formate in 25 grams of water, and 170 grams of mineral spirits was sparged with air at the rate of 30 liters per hour until the exotherm had subsided. Sparging with air was continued while the reaction mixture was heated at 95° C. for 5 hours. It was then heated to 135° C. under vacuum to remove water from it, filtered, and diluted with mineral spirits. There was obtained a solution of iron isooctanoate in mineral spirits that contained 9.0% of iron.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[NH2:17].[OH-].[Li+].O>C1COCC1.CO>[NH2:17][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc(CCN2CCCC2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCN2CCCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester (1.04 g, 4.19 mmol) in a mixture of THF (8 mL) and methanol (5 mL) was added lithium hydroxide (0.36 g), followed by water (3 mL). The reaction mixture was stirred at room temperature overnight, and then refluxed for 4 hours. After cooling to room temperature, the was solvent concentrated. The pH was adjusted to approximately 5 with 2 N aqueous hydrochloric acid and the residue was evaporated to dryness to give 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid as a chloride salt. Yield: 1.84 g. The crude material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[CH3:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH3:17][C:4]1[S:3][C:2]2[N:1]=[C:19]([CH3:21])[CH:18]=[C:7]([NH2:8])[C:6]=2[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: CC(C)=O
Reactant: COc1cccc(-c2c(C)sc(N)c2C#N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophenecarbonitrile (Description 3) (260 mg, 1.064 mmol) in toluene (2.5 mL), were added at RT, acetone (0.094 mL, 1.277 mmol) and SnCl4 (0.150 mL, 1.277 mmol), the reaction mixture was stirred for 5 min at RT then for 15 min at 150° C. in a microwave. The reaction mixture was cooled to RT then diluted with aqueous NaOH (1M) until the solution turned basic. The aqueous layer was then extracted with DCM (3×30 mL), the combined organic extracts were dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, afforded the title compound (167 mg). LCMS (A) m/z: 285 [M+1]+, Rt 1.20 min (basic).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[C:6]([CH2:9][C:10](=O)[CH3:11])(=O)[CH3:7].S(=O)(=O)(O)O>C(O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:9][C:10]([CH3:11])=[N:5][C:3]1=[O:4]
Reactant: CC(=O)CC(C)=O
Reactant: CNC(N)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(C)n(C)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g (0.262 mol) of N-methylurea and 29.4 g (0.291 mol) of acetylacetone were together dissolved in 100 ml of absolute ethanol. 97 g of concentrated sulfuric acid were then added, and the reaction mixture heated up. The mixture was then after-stirred for 1 hour at room temperature. After just a short time, the hydrogen sulfate salt of the product precipitated out in the form of a pale, crystalline solid, which was filtered off. This salt was dissolved in a small amount of water and the solution was rendered neutral using 10% strength sodium hydroxide solution. Extraction was then carried out by shaking with chloroform, and the solvent was dried with magnesium sulfate. After removing the solvent on a rotary evaporator, the desired product was produced in the form of pale pink-colored crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][O:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Cl[S:38](O)(=[O:40])=[O:39]>>[CH3:22][O:21][CH2:20][C:16]1[C:14]2[N:15]=[C:10]([C:5]3[CH:6]=[C:7]([S:38]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)(=[O:40])=[O:39])[CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])[NH:11][C:12](=[O:23])[C:13]=2[N:18]([CH3:19])[N:17]=1
Reactant: CN1CCNCC1
Reactant: CCOc1ccccc1-c1nc2c(COC)nn(C)c2c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(COC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
5-(2-Ethoxyphenyl)-3-methoxymethyl-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (470 mg, 1.50 mmol) was dissolved in chlorosulphonic acid (3 ml) at 0° C. The solution was stirred at room temperature for 2 hours, then cautiously added to ice-water (50 ml). The resulting solution was neutralised with saturated sodium carbonate solution, then extracted with a 20:1 mixture of dichloromethane and methanol (2×50 ml). The combined organic extracts were evaporated under vacuum and the residue was dissolved in ethanol (5 ml) and the solution treated with N-methylpiperazine (450 mg, 4.5 mmol). After 1 hour at room temperature the solvent was evaporated under vacuum and the residue chromatographed on silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonium hydroxide solution (90:10:1 by volume). Trituration of the crude product with ethyl acetate gave the title compound as a white solid (49 mg, 7%), m.p. 198°-199° C. Found: C,52.94; H,6.04; N,17.67. C21H28N6O5S requires C,52.93; H,5.92; N,17.64%.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)([CH3:4])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[H][H]>[Pt].C(OCC)(=O)C>[NH2:16][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:6]=1[NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: [H][H]
Reactant: CC(C)(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1c(N)cnc2ccccc12

Procedure:
A mixture of 17.7 g (0.0722 mole) of N-(1,1-dimethylethyl)-3-nitro-4-quinolinamine, 350 mL of ethyl acetate, 20 g of magnesium sulfate and about one gram of platinum on charcoal was hydrogenated on a Paar apparatus. After hydrogen pressure stabilized, the mixture was filtered and the filtrate was evaporated to provide a solid residue of 3-amino-N-(1,1-dimethylethyl)-4-quinolinamine.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:31].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:31][C:7]1[CH:8]=[C:9]([S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)COc1ccc(SCCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(SCCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-acetic acid methyl ester (0.78 g, 1.7 mmol) in 10 ml of tetrahydrofuran and 2.0 ml of water was treated with lithium hydroxide monohydrate (0.21 g, 5.0 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 5.0 ml of water and made strongly acidic by the addition of 4.0 N hydrochloric acid. The mixture was extracted with ethyl acetate (4×30 ml), and the combined extracts were washed with brine (2×50 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was recrystallized from ethyl acetate/hexane. mp 132-134° C.; IR (thin film) cm−1: 1741, 1709, 1490, 1326, 1239, 1110; 400 MHz 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.0 Hz), 7.74 (d, 2H, J=8.0 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.15 (m, 2H), 6.75 (d, 1H, J=8.3 Hz), 4.64 (s, 2H), 3.11 (t, 2H, J=7.6 Hz), 2.82 (t, 2H, J=7.6 Hz), 2.12 (s, 3H); MS m/z 447 (M+1). Anal. Calc'd for C24H21F3O3S: C, 64.56; H, 4.74. found: C, 64.45; H, 4.58.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH:18]=O)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][C:26]([CH3:28])=[O:27]>>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9](/[CH:18]=[CH:25]/[C:26](=[O:27])[CH3:28])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) was added 1N sodium hydroxide (19.3 mg) and acetone (0.425 mL) at ambient temperature. After 8 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=5-1) to give (3E)-4-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]-pyridazin-3-yl]-3-buten-2-one as an yellow solid (33 mg).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[C:22]3[S:23][C:24]([CH3:26])=[CH:25][C:21]=3[N:20]=[C:19]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])[CH2:29][CH2:28]3)[N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[OH-].[K+]>CO>[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[C:22]3[S:23][C:24]([CH3:26])=[CH:25][C:21]=3[N:20]=[C:19]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])[CH2:29][CH2:28]3)[N:18]=2)[CH2:12]1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3CCN(C(=O)OCc4ccccc4)C3)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3CCNC3)c2s1

Procedure:
To a suspension of benzyl-3-{[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthienopyrimidin-4-yl]amino}-pyrrolidine-1-carboxylate (300 mg, 0.55 mmol) in methanol (5 mL) was added an aqueous solution of potassium hydroxide (40%, 5 mL). The suspension was heated under reflux for 30 minutes. The organic solvent was removed by concentration in vacuo. The residue was purified by preparative HPLC to afford the pure product as a white solid. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (METHANOL-d4) δ ppm 7.73 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.1 Hz, 1H), 7.37-7.52 (m, 2H), 6.77-6.85 (m, 1H), 5.19 (d, J=15.4 Hz, 1H), 4.79-4.97 (m, 3H), 4.71 (br. s., 1H), 3.44 (d, J=3.0 Hz, 2H), 3.25-3.38 (m, 2H), 3.21 (d, J=5.8 Hz, 1H), 3.02-3.13 (m, 1H), 2.54 (s, 3H), 2.34 (td, J=12.9, 6.9 Hz, 1H), 1.95-2.07 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2C=CC(CNCC(O)=O)=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N[CH2:65][CH2:66][CH2:67][N:68]([CH3:70])[CH3:69])C.[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75]>CN(C=O)C>[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([O:14][C:15]2[CH:65]=[CH:66][C:67]([N:68]([CH2:69][C:74]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][C:39]4[CH:38]=[CH:37][C:36]5[O:31][CH2:32][CH2:33][O:34][C:35]=5[CH:40]=4)[CH2:43][CH2:44]3)=[O:75])[CH3:70])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(O)CNCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCCO2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)N1CCN(Cc2ccc3c(c2)OCCO3)CC1)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of ({4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (2.50 g, 5.6 mmol) in DMF (55 mL) were added 1-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazine (1.7 g, 7.3 mmol), 1-hydroxybenzotriazole monohydrate (0.86 g, 5.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in ethanol (30 mL). To the resulting solution was added maleic acid (0.32 g, 2.7 mmol), and this solution was left to stand. The precipitates were collected by filtration, to thereby yield 1.45 g of the title compound.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=1.CC1C=CC(S(O[CH2:32][CH2:33][CH2:34][F:35])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:35][CH2:34][CH2:33][CH2:32][O:13][C:10]1[N:11]=[CH:12][C:7]([C:6]2[CH:5]=[CH:4][N:3]3[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=[C:2]3[N:1]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccn3c(n2)nc2ccccc23)cn1
Reactant: Cc1ccc(S(=O)(=O)OCCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FCCCOc1ccc(-c2ccn3c(n2)nc2ccccc23)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To 5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-ol (8 mg, 0.03 mmol), and 3-fluoropropyl 4-methylbenzenesulfonate (21 mg, 0.09 mmol) in 0.3 mL of NMP was added Cs2CO3 (15 mg, 0.045 mmol). The reaction was stirred at rt for 4 h and diluted with EtOAc (10 mL). The mixture was washed with water (3×10 mL) and dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (water/MeCN with TFA buffer) to afford 2-(6-(3-fluoropropoxy)pyridin-3-yl)benzo[4,5]imidazo[1,2-a]pyrimidine as a off-white solid (3 mg, 31%). 1H NMR (400 MHz, methanol-d4): δ 9.79 (d, J=7.2 Hz, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.69 (dd, J=8.8, 2.8 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.29 (d, J=7.2 Hz, 1H), 7.90-7.82 (m, 2H), 7.72 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 4.57 (t, J=6.4 Hz, 2H), 4.56 (t, J=5.6 Hz, 1H), 2.30-2.16 (m, 2H); MS (ESI) m/z [M+H]+323.
Reaction SMILES: Br.[CH3:2][N:3]1[N:7]=[N:6][C:5]([C:8]2[CH2:9][NH:10][CH2:11][CH2:12][CH:13]=2)=[N:4]1.[CH:14](O)=O>C=O>[CH3:2][N:3]1[N:7]=[N:6][C:5]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4]1
Reactant: O=CO
Reactant: Cn1nnc(C2=CCCNC2)n1
Agent: Br
Agent: C=O
Product: CN1CCC=C(c2nnn(C)n2)C1
Yield: 74 %

Procedure:
A solution of 8 (0.70 g, 0.0028 mol) in formic acid (20 ml) and 35% formaldehyde (7 ml) was refluxed overnight. The solution was evaporated in vacuo, and the residue was taken up in ether (20 ml) and 28% sodium hydroxide (20 ml). The phases were separated, and the aqueous phase was extracted three times with dichloromethane (20 ml). The combined organic phases were washed four times with saturated sodium chloride solution (20 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo yielding 0.60 g of crude 10. Crystallization from ether - light petroleum gave 0.37 g (0.0021 mol, 74%) of title compound, M.P. 86°-87° C. Anal. (C8H13N5) C, H, N.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].CO>ClCCl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: OCCO
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(Cl)cc2)OCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 55.4 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), ethylene glycol (1.7 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxolane (21) as a colourless oil (1.1 g, 51%). 1H nmr (300 MHz, CDCl3) 1.63 (s, 3H, CH3), 3.72-3.82 (m, 2H, OCH2), 3.98-4.09 (m, 2H, OCH2), 7.42 (d, J=8.6 Hz, 2H, 2×ArH), 7.30 (d, J=8.6 Hz, 2H, 2×ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:15]([O:17][C:18](=[O:33])[C:19]([CH2:31]O)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:31][O:13][C:12](=[O:14])[CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:33])[CH3:24]
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Reactant: Cc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(COC(=O)Cc1ccc([N+](=O)[O-])c(C)c1)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
The (3-Methyl-4-nitrophenyl)acetic acid (0.143 g) obtained in Example 1-3b) was dissolved in methylene chloride (5 mL). To the solution were added 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (0.195 g) obtained in Example 1-2a), 4-dimethylaminopyridine (0.090 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.141 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to give the title compound (0.219 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(Cl)nc2c1c(-c1ccncc1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.05 g, 0.11 mmol), Pd(PPh3)2Cl2 (0.015 g, 0.022 mmol) and pyridine-4-ylboronic acid (0.03 g, 0.24 mmol) in p-dioxane (0.7 mL) was added a solution of Na2CO3 (0.035 g, 0.33 mmol) in water (0.3 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.02 g).