Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]([O:32][CH3:33])(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O-])=[O:29]>>[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:29])([O:32][CH3:33])=[O:31]
Reactant: CCOC(=O)CCCOc1cccnc1N
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Product: CCOC(=O)CCCOc1cccnc1NC(=O)CCCCCCCCCCC(=O)OC

Procedure:
When (41) and (7) are reacted as per the procedure of step (E), above, the title compound (42) is obtained. Hydrolysis will yield the corresponding di-acid (4-(2-(11- Carboxyundecanoylamino)pyrid-3-yloxy)butyric acid (43).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([Mg]Br)[CH3:12].C(=O)=O.CC(C)=O>CCOCC>[O:4]=[C:2]([CH2:11][CH3:12])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC[Mg]Br
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CC
Yield: 85.9 %

Procedure:
Diethyl oxalate (10 g; 68 mmol) was dissolved in Et2O (100 ml) and cooled to −78 C. Ethyl magnesium bromide (1.0 M in THF; 72 ml; 71.8 mmol; 1.05 equiv.) was added slowly via syringe. The dry ice/acetone bath was allowed to melt and warm to 10 C. Monitored the reaction by 1H NMR. The reaction was cooled to 0 C and quenched with saturated NH4Cl. Dilute with H2O and separate phases. The organic layer was dried over Na2SO4, filtered and concentrated. Isolation gave 7.6 g of a crude yellow oil in 86% yield. No further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1Br.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1sc(Br)c(Br)c1O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccnn2C)c(Br)c1O
Reaction time: 12 h
Yield: 14.9 %

Procedure:
Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (339 mg, 1.75 mmol), Pd(PPh3)4 (92 mg, 79.4 μmol) and K2CO3 (876 mg, 6.35 mmol) in dioxane (6.6 mL) and H2O (1.3 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (75 mg, 15%) as a brown residue: LCMS (ES) m/z=318 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1.Cl>CO.O>[CH3:24][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1[N+](=O)[O-]
Temperature: 125 °C
Yield: 22.3 %

Procedure:
4-hydroxybenzoic acid (13.8 g, 0.1 mole) was dissolved in methanol and to this solution was added, sodium methoxide (10.8 g, 0.2 mole). The solution was then evaporated to dryness. To the resulting solid was added DMF (500 mL) followed by 4-fluoro-2-methyl-1-nitrobenzene (available from Aldrich under 5-fluoro-2-nitro-toluene) (10.2 mL 0.1 mole). The mixture was heated at 125° C. for 2 hours, cooled and poured into 3 L of water, acidified to pH2 with 2M HCl and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried and evaporated to dryness. The resulting solid was triturated with ether to give 4-(3-methyl-4-nitro-phenoxy)-benzoic acid (compound 1) as a white solid 6.1 g (22% yield; melting point=187-190° C.).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([N:15]3[CH2:25][CH2:24][C:18]4[N:19]=[C:20]([NH2:23])[N:21]=[CH:22][C:17]=4[CH2:16]3)=[CH:13][CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=3)[CH2:25][CH2:24][C:18]=2[N:19]=1
Reactant: COc1ccc(COc2ncccc2N2CCc3nc(N)ncc3C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc2c(n1)CCN(c1ccc[nH]c1=O)C2
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A solution of 6-{2-[(4-methoxybenzyl)oxy]pyridin-3-yl}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1.77 g, 4.87 mmol) in dichloromethane (70 ml) was treated with trifluoroacetic acid (2.68 ml, 36.04 mmol) at room temperature. After stirring for 30 minutes, the solvent and excess acid was removed in vacuo and the residue was treated with ethyl acetate. Washing with sat'd NaHCO3(aq.) gave a yellow, amorphous precipitate. The solid was collected, washed with water, EtOAc, MeOH and dried (774 mg, 65%). The product was suspended in a 2:1 (v/v) mixture of water: MeOH (125 ml) and heated to boiling with vigorous stirring for 1.5 hours. The undissolved solid remaining was collected by filtration while the mixture was still hot and washed with water, MeOH, and dried to give the title compound (478 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[CH:11]=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].Cl>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[CH:11]=[O:12])[C:5]([NH:21][CH3:20])=[O:6]
Reactant: O=Cc1c(F)cc(C(=O)O)cc1F
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To an ice-cold solution of 3,5-difluoro-4-formylbenzoic acid (120 g, 645 mmol) in dichloromethane (1.5 L) and N,N-dimethylformamide (2.0 g, 27 mmol) was added oxalyl chloride (90 g, 709 mmol) drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 10° C. The resulting mixture was stirred at the same temperature for 0.5 hr, warmed to room temperature, and stirred for an additional 1.5 hr. The solution was then cooled to 0° C., and aqueous methylamine (40%, 168 mL, 1.94 mol) was added drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 7° C. Afterward, the mixture was quenched with aqueous HCl (2M, 335 mL, 670 mmol) and warmed to room temperature. The organic layer was separated, washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under vacuum. The resulting residual solid was taken in MTBE (500 mL), and the resulting mixture was heated to reflux for 0.5 hr, cooled to room temperature, and stirred for 18 hr. Afterward, the mixture was cooled to 0° C., filtered, rinsed with pentane, and dried under vacuum to form the title compound (103 g, 80%) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 3.03 (d, J=4.86 Hz, 3H), 6.37 (br s, 1H), 7.36-7.42 (m, 2H), 10.36 (s, 1H); MS m/z 200.06 [M+H]+ (ESI).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH2:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][C:20]#[CH:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: C#CCCCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Yield: 40.8 %

Procedure:
A solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (56 mg, 0.2 mmol; see Examples 1 and 2 above), pent-4-ynyl-benzene (44 mg, 0.3 mmol), Pd(PPh3)4 (26 mg, 0.03 mmol), CuI (4 mg, 0.03 mmol), PPh3 (8 mg, 0.03 mmol), and TEA (11 μL, 2.5 mmol) in DMF (5 mL) was heated (at around 105° C.) under N2 for 2 hours. The reaction was diluted with EtOAc (15 mL) and washed with brine (3×10 mL) and dried with MgSO4. The solvent was removed and the reaction purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a brown solid (28 mg,). 1H NMR (400 MHz, DMSO-d6) δ 1.85 (quin, J=7.5 Hz, 2H) 2.44 (t, J 7.1 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 6.72 (dd, J=3.4, 1.8 Hz, 1H), 7.14 (dd, J=3.5, 0.8 Hz, 1H), 7.2-7.30 (br m, 5H), 7.92 (dd, J=1.7, 0.8 Hz, 1H), 8.35 (s, 1H). MS: m/z 344 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Zn+])=[O:6])[CH3:3].[C:14]1([C:20]2([C:23](Cl)=[O:24])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O.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:14]1([C:20]2([C:23]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[O:24])[CH2:21][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Reactant: CCOC(=O)c1ccccc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12].[K].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:14]([NH:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(O)n(N)c(=O)c1C#N
Reactant: O=C(Cl)c1ccccc1
Agent: [K]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)n(NC(=O)c2ccccc2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
To a solution of 10.16 g (50 mmol) of potassium 1-amino-5-cyano-2-hydroxy-4-methyl-6-pyridone in 50 ml of water was added a solution of 7.03 g (50 mmol) of benzoyl chloride in 50 ml of methylene chloride. The mixture was stirred rapidly for 1 hr, and then filtered. The solid was washed with isopropanol and air dried. The yield of product was 3.90 g (29.0%); mp: 256° C. dec. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C14H11N3O3: C, 62.5; H, 4.1; N, 15.6. Found: C, 62.23; H, 4.31; N, 15.85.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([F:10])[C:3]=1[Cl:11].[NH3:12]>C(#N)C>[NH2:12][C:6]1[C:7]([F:8])=[C:2]([Br:1])[C:3]([Cl:11])=[C:4]([F:10])[N:5]=1
Reactant: N
Reactant: Fc1nc(F)c(Cl)c(Br)c1F
Solvent: CC#N
Product: Nc1nc(F)c(Cl)c(Br)c1F
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 20 ml of acetonitrile were added 4.9 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 4 ml of 25% aqueous solution of ammonia, and the mixture was stirred at 55° C. for 2 hours. The solvent and the like were distilled off under reduced pressure. 50 ml of chloroform was added to the residue, and the solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dispersed in the mixed solution of diisopropylether and n-hexane and collected by filtration to obtain 3.8 g of the title compound as pale yellow needle crystals.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[K+].[K+]>>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[N:31][CH:32]=3)[N:7]2[CH:8]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1

Procedure:
Compound 1e was subjected to Suzuki coupling conditions with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the reaction conditions described in Example 1, Step G, and substituting K2CO3 as the base to obtain compound 23a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H33N7O4: 496.3 (M+H). Found 496.3.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[O:15][C:11]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2ccc(O)cc2o1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
To a stirred solution of 393 (1.2 g, 4.26 mmol) in MeOH (20 mL) was added palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered off through Celite and the filtrate was evaporated via rotary evaporation, and the resulting solid dried under vacuum to afford 394 as a white solid (700 mg, 86%).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:12][Cl:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (1.5 g, 0.006 mol) and acetic anhydride (4.3 g, 0.042 mol) in dry acetone (50 mL), triethylamine (3.6 g, 0.035 mol) was added dropwise at room temperature. After an additional 16 h, the reaction mixture was evaporated to dryness. The residue was taken up in ethyl acetate (50 mL) and washed with dilute hydrochloric acid (3×10 mL), followed by water (3×10 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, treated with charcoal and filtered. On evaporation of the solvent a solid was obtained which, on recrystallization from ethanol, gave 1.1 g (62.8%) of the title compound: mp 148°-149° C.; 1H NMR (acetone-d6) δ 3.8-4.2 (m, 4 H, CH2CH2), 3.5 and 3.3 (2 s, 6 H, 2CH3SO 2), 2.4 (s, 3 H, CH3CO). Anal. (C6H13C1N2O5S2) C, H, N.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>C(Cl)Cl>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:37]
Reactant: CNCCN(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CCN(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N,N′-trimethylethylenediamine (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 534 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3C)c2cc1OC
Temperature: 139 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.156 g (1.1 mmol) of 4-chloro-2-methylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 24 hours; progress of the reaction was monitored by TLC. After 24 hours an additional 0.156 g of of 4-chloro-2-methylaniline was added and the heating continued for 24 hours. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The gummy solid was dissolved in chloroform and passed through a pad of hydrous magnesium silicate. The liquid was concentrated in vacuo and the residue triturated 5 times with hexane. The resulting precipitate was collected, washed with hexane, and dried in vacuo at 65° C. to give 0.250 g (71%) of the desired product as brown crystals. MP 227-229° C.;: mass spectrum (electrospray, m/e,): 353.8(M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[NH4+]>COCCOC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Microencapsulated Pd(OAc)2 (prepared as described in Example 1, 0.25 g, 2 mol %, based on palladium content) was added to a solution of 4-bromo nitrobenzene (1 mmol), trimethylphenyltin (1.5 mmol) and ammonium acetate (3 mmol) in 1,2-dimethoxyethane (5 mL) and stirred at 90° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with ether (50 mL) and filtered through a polyethylene frit (20-micron porosity). The filtrate was washed with water (2×20 mL), brine (20 mL) and dried (MgSO4). Evaporation under reduced pressure and purification by column chromatography gave 4-nitrobiphenyl, 90%: IR, 1H NMR and 13C NMR identical with sample obtained from the Suzuki reaction in Example 5.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH3:28])[NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16].CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-trifluoromethylphenyl glyoxal (2.1 g) and 2-(4-carbomethoxyphenyl)-1-methylethanamine (2.0 g) in benzene (150 ml) was refluxed under Dean & Stark conditions for 2 hours. The solvent was replaced with methanol (150 ml), the mixture was cooled in ice and sodium borohydride (4.0 g) was added portionwise. The mixture was stirred at ambient temperature for 3 hours, the solvent was evaporated and the residue was partitioned between water (100 ml) and chloroform (100 ml). The aqueous phase was further extracted with chloroform (100 ml), the combined organic extracts were dried (Mg SO4) and evaporated to an oil which was crystallised from hexane to give the title compound, m.p. 80°-83° as a 25:75 mixture of diastereoisomers. (25% RR,SS:75% RS,SR). τ(CDCl3) 8.95 (3H,d,J=6 Hz) 6.6-7.6 (5H,m), 6.13 (3H,s), 5.3 (1H,m) 2.72 (2H,d,J= 8 Hz), 2.1-2.5 (4H,m), 1.92 (2H,d,J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH:6][CH2:12][CH2:11][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: C=CS(C)(=O)=O
Reactant: Nc1c(F)cc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CCNc1c(F)cc(Cl)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.5 g, 1.8 mmol), vinylmethylsulfone (0.2 g, 1.8 mmol), Cs2CO3 (1.17 g, 3.6 mmol) and DMF (15 mL) was heated with stirring at 50° C. overnight. The resulting mixture was poured into water and then extracted with EA (50 mL×3). The combined organic phases were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (EtOAc:PE=1:40) to give 4-chloro-2-fluoro-6-iodo-N-[2-(methylsulfonyl)ethyl]aniline (0.42 g, yield: 61%).