Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](SC)[CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:17]C[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O.O[O:34][S:35]([O-:37])=O.[K+]>C1COCC1.CO>[CH3:17][S:35]([C:11]1[CH:10]=[C:9]([C:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:37])=[O:34]
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: O=S([O-])OO
Reactant: CSc1cccc(C2(O)CCC(=O)CC2)c1
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cccc(C2=CCC(=O)CC2)c1
Reaction time: 8 h

Procedure:
A solution of 4-hydroxy-4-(3-methylsulfanyl-phenyl)-cyclohexanone (as prepared in the previous step, 1.10 g, 4.66 mmol) in THF (10 mL) was treated with Burgess' reagent (1.20 g, 5.00 mmol) at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated to give a white solid. To this white solid in MeOH (5 mL) and water (5 mL) was added OXONE (Aldrich, 6.10 g, 10 mmol) at room temperature. The reaction mixture was stirred overnight and quenched with saturated NaHCO3. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23][CH3:24])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23]([CH3:24])=[O:34])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a cold (0° C.) solution of 6-[2-(benzyloxy)phenyl]-4-(methylthio)-2-oxo-1,2-dihydro-nicotinonitrile (4.00 g, 11.5 mmol) in CH2Cl2 was added m-chloroper-benzoic acid (mCPBA) (69%, 3.45 g, 13.8 mmol) in one portion. The reaction mixture was stirred at 0° C. to room temperature for 1 hr, quenched with saturated NaHCO3 solution (80 mL) including Na2S2O3.5H2O (5 g), and diluted with CH2Cl2. The separated organic phase was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual solid was triturated with diisopropyl ether to give 6-[2-(benzyloxy)phenyl]-4-(methylsulfinyl)-2-oxo-1,2-dihydro-nicotinonitrile as a yellow solid (4.00 g, yield; 96%).
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4].[C:14](=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.O>[C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1csc(C(=O)O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyliodide (783 mg, 5.51 mmoles) was added to a stirred suspension of 4-acetyl-2-thiophenecarboxylic acid (prepared according to Satonaka, H., Bull. Chem. Soc. Japan 56:2463 (1983)) (782 mg, 4.59 mmoles) and sodium carbonate (1.70 g, 16.08 mmoles) in 25 ml of N,N-dimethylformamide. After stirring overnight at room temperature the mixture was poured into water (125 ml), saturated with solid sodium chloride and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo to an off-white solid (761 mg, 90%), m.p. 94-6° C. EIMS (m/z): 184 (M+, 74%), 169 (M+ --CH3, base), 153 (M+ --CH3O, 51%); 1HNMR (DMSO-d6) delta, 8.17 (1H, d, J=1.5 Hz), 8.13 (1H, d, J=1.5 Hz), 3.88 (3H, s), 2.51 (3H, s).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(C1[N:9]([CH:42]([CH3:44])[CH3:43])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:41])(=[O:40])[N:27]([CH2:36][CH2:37][O:38][CH3:39])COCC[Si](C)(C)C)=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:12]=1)=O>CCCCCC.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:2]([C:1]1[N:9]([CH:42]([CH3:44])[CH3:43])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:40])(=[O:41])[NH:27][CH2:36][CH2:37][O:38][CH3:39])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:12]=1)=[CH:3][CH3:4]
Reactant: [Li]CCCC
Reactant: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
n-Butyl lithium (656 μl of a 1.6 N solution in hexane, 1.05 mmol), was added dropwise to a solution of ethyl triphenylphosphonium iodide (437 mg, 1.05 mmol), in anhydrous THF (15 ml), under nitrogen at 0° C. A solution of 4-(2-formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 105; 300 mg, 0.523 mmol), in THF (5 ml), was then slowly added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The volatiles were removed by evaporation and the residue dissolved in EtOAc (40 ml), washed with water (2×15 ml), brine (15 ml), and dried. The solvent removed by evaporation to give a crude product (254 mg), as a yellow foam. The crude product was purified by chromatography on silica-gel eluting with 3% MeOH in DCM), the semi-pure product (70 mg), was dissolved in TFA/H2O (1:1, 10 ml), and stirred for 1 hour. The TFA was removed by evaporation, the resulting aqueous solution neutralised with saturated NaHCO3, and the product extracted with DCM (3×5 ml). The extracts were combined, dried and the solvent removed. The residue was purified by preparative reverse phase HPLC, eluting with acetonitrile/H2O, 0.01% formic buffer. Pure fractions were neutralised with 2N aqueous sodium hydroxide solution. The resulting white precipitate, was collected by filtration and dried to give the title compound (1:2.5 mixture of E:Z isomers), as a white solid (5 mg, 2%). NMR: Z isomer 1.51 (d, 6H), 2.09 (d, 3H), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.05 (m, 1H), 6.51 (m, 1H), 7.1 (br s, 1H), 7.16 (d, 1H), 7.57 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.48 (d, 1H), 9.47 (s, 1H); E isomer 1.51 (d, 6H), 1.94 (d, 3H), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.60 (m, 1H), 6.67 (m, 1H), 7.1 (br s, 1H), 7.13 (d, 1H), 7.47 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.44 (d, 1H), 9.47 (s, 1H); m/z: 457.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29]Cl>CN(C)C=O>[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29][O:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N(C)C)nc2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
Sodium hydride (0.25 g) is added in small portions at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (3.1 g) in anhydrous dimethylformamide (50 cc). The suspension obtained is stirred for 45 minutes at a temperature in the region of 0° C., and N,N-dimethyl-2chloroacetamide (1.3 g) is then added. The reaction mixture is heated with stirring to a temperature of 70° C. for 3 hours, then cooled to a temperature in the region of 10° C., poured into distilled water (200 cc) and extracted with dichloromethane (3×70 cc). The organic phases are combined, washed with distilled water (2×40 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, N,N-dimethyl-2-[2-(7-methoxy-1,8-naphthyridin-2-yl)- 3-oxo-1 -isoindolinyloxy]acetamide (2 g), m.p. 166° C., is obtained.
Reaction SMILES: [N:1]1([C:6]2[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1([O:22][C:23](=O)[NH:24][C:25]2[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>O1CCOCC1.O>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([O:33][CH3:34])[N:26]=[C:25]([NH:24][C:23]([NH:15][S:12]([C:11]2[C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:7][CH:8]=[CH:9][CH:10]=2)(=[O:13])=[O:14])=[O:22])[N:30]=1
Reactant: NS(=O)(=O)c1cccnc1-n1cncn1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2-n2cncn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension containing 0.5 g of the sulfonamide prepared in Example 4 in 10 ml of p-dioxane was added 0.6 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.33 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The suspension was stirred at room temperature for about two hours then diluted with about 75 ml of water to form a solution. After acidifying the solution with conc. hydrochloric acid (red to litmus) and stirring 0.5 hour, a precipitate formed. The mixture was filtered and the isolated solid was washed with 10 ml water and suction-dried for 24 hours to yield 0.7 g of the subject compound; m.p. 226°-230°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:34])[C:28]2[S:33][CH:32]=[CH:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:34])[CH:28]5[S:33][CH:32]=[CH:31][CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: O=c1[nH]c(CCl)nc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5C=CSC5C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 91.2 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 2-chloromethyl-3H-thieno[3,2-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C24H26N4O4S 466.5632. found (ESI, [M+H]+) 467.1740. 1H NMR (400 MHz, MeOD) δ ppm 1.65-1.92 (m, 4H) 2.06-2.29 (m, 2H) 2.48-2.62 (m, 1H) 2.78-2.89 (m, 1H) 2.89-3.00 (m, 1H) 3.09-3.18 (m, 1H) 3.34-3.53 (m, 4H) 3.55-3.65 (m, 1H) 3.68-3.77 (m, 1H) 4.23-4.32 (m, 1H) 4.60-4.69 (m, 1H) 6.97 (d, J=9.03 Hz, 2H) 7.17-7.24 (m, 1H) 7.73-7.81 (m, 1H) 7.96 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=2.77 min
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:21][C@H:16]1[N:15]([C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)[N:4]=2)[CH2:20][CH2:19][N:18]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:17]1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-Methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (1.50 g, 5.24 mmol) in dimethyl sulufoxide (10.0 ml) was added 4-fluorobenzonitrile (1.27 g, 10.5 mmol), potassium carbonate (2.90 g, 21.0 mmol), and the reaction mixture was stirred for 12 hours at 120° C. The reaction was quenched with water, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. After removal of the solvent, the precipitate was filtered, washed with ether, and dried to give 4-[(3R)-3-Methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.70 g, 4.39 mmol, 84%) as pale yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([Cl:21])(=[O:20])=[O:19]>ClC(Cl)C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:16][C:15]1[C:10]([Cl:9])=[C:11]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)C(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)c(CBr)c1Cl
Temperature: 120 °C
Yield: 47.1 %

Procedure:
85.44 g (0.48 mol) of N-bromosuccinimide and then 200 mg of benzoyl peroxide are added to a solution, at room temperature, of 41.52 g (0.16 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 150 ml of 1,1,2,2-tetrachloroethane. The reaction mixture is heated at 120° C. for 2 hours. It is cooled and filtered and the filtrate is washed successively with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. The organic phase collected from the filtrate is then dried over magnesium sulfate and concentrated. Recrystallization from hexane gives 25.53 g of the expected product in the form of white crystals (yield =47%).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>C(O)(C)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: ClCCCCBr
Reactant: OCc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: OCc1ccccc1SCCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, thermowell, and addition funnel, under a nitrogen atmosphere, was added 150.0 g of o-mercaptobenzyl alcohol, 2400 ml of isopropanol and 295.72 g of anhydrous potassium carbonate. The reaction mixture was cooled in an ice bath, as 246.6 ml of 1-bromo-4-chlorobutane was added dropwise. After addition was complete, the mixture was allowed to warm to room temperature, and stirred at room temperature overnight. The mixture was filtered through a pad of filter aid, and the solid was rinsed with fresh isopropanol. The solvent was removed by rotary evaporation to give 246.0 g of the product as a brown oil. 1H-NMR (CDCl3) δ 1.7-2.1(m,4H); 2.3(br s,1H); 2.85-3.0(t,2H); 3.5-3.6(t,2H); 4.75(s,2H); 7.2-7.4(m,4H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22]>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22]
Reactant: BrCCCC/C=C\C=C/CCCCBr
Reactant: Cc1ccnc(C)c1
Solvent: CC#N
Product: Cc1cc[n+](CCCC/C=C\C=C/CCCC[n+]2ccc(C)cc2C)c(C)c1
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 2,4-lutidine (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no 2,4-lutidine left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.31 (d, J=6.3, 2H), 7.53 (s, 2H), 7.46 (d, J=6.9, 2H), 6.16-6.22 (m, 2H), 5.32-5.40 (m, 2H), 4.28 (t, J=8.1, 4H), 2.58 (s, 3H), 2.38 (s, 3H), 2.07 (q, J=7.2, 4H), 1.74 (p, J=7.5, 4H), 1.33 (p, J=7.5, 4H). CNMR, 159.20, 153.87, 143.69, 132.32, 130.44, 126.34, 124.18, 57.19, 29.10, 26.41, 25.63, 21.19, 19.46.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32](I)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc2c(I)c(F)ccc2s1
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1c(-c2c(F)ccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-butoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo-5-fluorobenzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thiophene.
Reaction SMILES: [CH2:1]1[CH:5]([OH:6])[CH2:4][NH:3][CH2:2]1.[C:7]1([NH:13][C:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.CO>C(O)CCC>[C:7]1([NH:13][C:14]([C:16]2[CH:21]=[C:20]([N:3]3[CH2:2][CH2:1][CH:5]([OH:6])[CH2:4]3)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CCNC1
Reactant: O=C(Nc1ccccc1)c1cc(Br)ccn1
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Solvent: CO
Product: O=C(Nc1ccccc1)c1cc(N2CCC(O)C2)ccn1
Yield: 61.5 %

Procedure:
A solution of dl-3-pyrrolidinol (0.17 g, 1.95 mmol) and 4-bromo-pyridine-2-carboxylic acid phenylamide (0.36 g, 1.3 mmol) in 1-butanol (25 mL) was heated at 100° C. for 15 hours. The reaction was applied to silica gel (25 g) and eluted with chloroform then chloroform:methanol 9:1 to give the title compound 227 mg (0.80 mmol, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].[NH3:16]>C(N)=O>[NH2:16][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[CH2:9][CH2:10][OH:11]
Reactant: N
Reactant: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)OCC2
Solvent: NC=O
Product: Nc1c(CCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
0.17 Mole (35.7 g) of 2,3-dihydro-5,7-dinitrobenzofuran, prepared according to Chatelus Ann. Chim. [12], 4,505-547 (1949), is suspended in 350 ml of 20% strength ammonia solution and 220 ml of formamide. After 8 hours' heating at 110° C., a further 100 ml of 20% strength ammonia solution are added. Heating is maintained for 4 hours. When the reaction medium is cooled, the expected product precipitates.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[C:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[CH:24][CH:23]=1)([OH:20])=[O:19]>C1COCC1>[ClH:10].[C:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(CC(=O)O)cc1
Agent: I
Solvent: C1CCOC1
Product: Cl
Product: N=C(NCCCCc1ccc(CC(=O)O)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 46.5 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.2 g, 0.5 mmol) was added to a solution of 8 (0.7 g, 3.4 mmol) in THF (20 mL). The reaction mixture was stirred at reflux for 6 h, then the solvent was evaporated and the resultant oil was treated with 10% HCl (15 mL). The precipitate was isolated and crystallized twice from ethanol to give 9 (53 mg, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.59 (br s, 4H), 2.71 (m, 2H), 3.83 (s, 3H), 7.40 (d, 2H), 7.48 (br s, 2H), 7.80 (d, 2H), 8.92 (br s, 2H), 9.00 (br s, 1H), 9.48 (br s, 2H), 10.55 (s, 1H). APCI MS m/z=420 [C18H22ClN7O3+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14].ClCCl.CO>C(O)C>[CH2:1]([C@H:8]([CH2:13][CH2:12][OH:11])[C:9]([NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCC[C@H]1Cc1ccccc1
Reactant: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: NC(=O)[C@@H](CCO)Cc1ccccc1
Yield: 63.8 %

Procedure:
(R)-2-benzylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (R)-2-benzyl-4-hydroxybutyramide.
Reaction SMILES: [Cl:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Na+].[I-]>CO>[ClH:1].[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: C1COCCN1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
To a solution of 500 mg (2 mmol) 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in 4 ml of MeOH was added 227 mg (2.6 mmol) of morpholine and 150 mg NaI. The mixture was stirred at RT for 3 days. The solvent was removed and the residue dissolved in 5 ml of ether, followed by titration with 4N HCl-dioxane to obtain a precipitate. Recrystallization from isopropanol/ether produced 200 mg of pure 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-morpholinopropan-1-one hydrochloride. Compound 1034.