Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12](/[C:15]2[CH:19]=[C:18]([Cl:20])[S:17][CH:16]=2)\[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:28][NH2:29]>CO>[Cl:20][C:18]1[S:17][CH:16]=[C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](\[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:29][CH3:28])=[CH:6][CH:7]=2)[CH:19]=1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1csc(Cl)c1
Reactant: CN
Solvent: CO
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1csc(Cl)c1
Yield: 35 %

Procedure:
Following the same procedure as described in example 11, step D, (E)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(5-chlorothiophen-3-yl)but-1-enyl)phenol (0.8 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) at reflux to give 120 mg desired product (35% yield, E). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (bs, 1H), 6.99-7.02 (m, 3H), 6.84-6.89 (m, 2H), 6.62-6.70 (m, 2H), 6.50-6.56 (m, 3H), 3.97 (t, J=5.6 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.26-2.38 (m, 5H), 0.89 (t, J=7.2 Hz, 3H); m/z=414[M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylethanolamine (5.02 ml, 50 mmol) was added dropwise over 5 minutes to an ice-cooled suspension of sodium hydride (2.2 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (100 ml), and the solution was stirred for 30 minutes. tert-Butyl bromoacetate (7.38 ml, 50 mmol) was added dropwise over 5 minutes, then the mixture was allowed to warm to room temperature and stirred for a further 18 hours. The mixture was pre-adsorbed onto silica gel, and purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate:methanol (50:50:0 to 0:100:0 to 0:80:20) to afford the title compound as a yellow oil, 1.46 g. 1H-NMR (CDCl3, 400 MHz) δ: 1.50 (s, 9H), 2.30 (s, 6H), 2.59 (t, 2H), 3.64 (t, 2H) 4.00 (s, 2H). LRMS: m/z (ES+) 204 [MH+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C(C)=CC=CC=1C.[C:17](Cl)(=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:26])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3-bromoaniline (13.1 mL, 120 mmol) in dichloromethane (100 mL) and 2,6-lutidine (21 mL, 180 mmol) at 0° C. was added a solution of cinnamoylchloride (20 g, 120 mmol) in dichloromethane (50 mL) dropwise. The reaction mixture was allowed to reach room temperature and was stirred for 2 hours. It was quenched with potassium phosphate buffer (100 mL, 1M, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (200 mL), dried over sodium sulfate and concentrated to dryness. The residue was crystallized from toluene/hexanes to give the product as colorless solid (33.4 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]2=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2[nH]nnc2c1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nc2ccccc2n1

Procedure:
Using general procedure 4 and purification method E (elute with isocratic 20% ethyl acetate/hexanes in this case) with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and 1,2,3-benzotriazole (0.136 g, 1.14 mmol) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17][CH2:18][O:19][C:20]([CH2:22][C:23]#[N:24])=[O:21].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:18]([O:19][C:20](=[O:21])[C:22]([C:23]#[N:24])=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([CH3:16])([CH3:15])[CH2:7]1)[CH3:17]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
122 g (0.55 mol) of 2,3-Dihydro-5,6-dimethoxy-3,3-dimethyl-1H-inden-1-one (CAS N.[4136-26-9] for preparation see F. Camps, Z. Naturforsch., B : Anorg. Chem., Org. Chem. (1984), 39B (12), 1801-5), 63,3 g (0.56 mol) of ethyl cyano acetate, 12 g (0.14 mol of piperidine, 12 g (0.1 mol) of benzoic acid and 1000 ml toluene were mixed together and heated under reflux for 48 hours. The reaction mixture was cooled to room temperature, washed with diluted HCl, aqueous Na2CO3, and water and then dried (MgSO4). Removal of the solvent and crystallization from EtOH gave 123.8 g of a yellow solid (m.p.: 148-149° C). Yield: 71%; E1%cm: 790 (1 max.: 367 nm) in EtOH. Solubility: 0.35% in CÉTIOL LC
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[O:23]1[CH:27]=[CH:26][C:25]([NH:28][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])=[N:24]1
Reactant: Nc1ccon1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccon1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (854 mg, 2.17 mmols) and isoxazol-3-amine (0.48 ml, 6.50 mmols). The title compound was obtained (919 mg, 55% purity, 64%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][CH2:5][C:6](=[CH2:9])[CH:7]=[CH2:8].CO>C1COCC1.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>[CH3:8][CH2:7][C:6]([CH2:5][CH2:4]/[CH:3]=[C:2](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])\[CH3:1])=[CH2:9]
Reactant: C=CC(=C)CC/C=C(\C)CCC=C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: C=C(CC)CC/C=C(\C)CCC=C(C)C
Temperature: 90 °C
Reaction time: 64 h
Yield: 115.9 %

Procedure:
In a 75 mL Keim autoclave, containing a stirring bar, were placed (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene (1.00 g, 4.89 mmol) in THF (20 ml). Methanol (200 μl, 4.94 mmol) and PdCl2(PPh3)2 (80 mg, 0.114 mmol) were added. Then the reactor was sealed and the mixture purged with 3×10 bar of carbon monoxide (CO). While stiffing, the autoclave was pressurized to 40 bar with CO and then heated in an oil bath at 90° C. Once the temperature equilibrated to the set point, the autoclave was pressurized to 67 bar with CO and the reaction allowed to proceed under these conditions for 64 h. Then the reaction mixture was concentrated on a rotary evaporator to give a crude residue which was subsequently distilled on a Kugelrohr apparatus (0.3 mbar/170° C.) to afford a colorless liquid (1.17 g) containing (3E,7E)-homofarnesic acid methyl ester and (3Z,7E)-homofarnesic acid methyl ester (61%, 2/1).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH2:23]>CO>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:23])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Reactant: O
Solvent: CO
Product: COc1ccc(S(=O)C(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mol) in Example 1) was dissolved in methanol (100 ml) and 30% H2O (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C. and quenched with saturated Na2SO3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl3 and washed with H2O. The organic layer was dried over MgSO4, filtered and concentrated. The title compound isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; 1H NMR (300 MHz, CDCl3): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.N1CCCCC1.[Cl:20][CH2:21][CH:22]1[O:24][CH2:23]1>>[Cl:20][CH2:21][CH:22]([OH:24])[CH2:23][O:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Solvent: C1CCNCC1
Product: Cc1cc(=O)c2ccc(OCC(O)CCl)cc2o1

Procedure:
17.6 g 7-hydroxy-2-methyl-4H-1-benzopyrane-4-one-[J.Org. Chem. 24, 683, (1959)], 0.1 cm3 piperidine and 60 cm3 1-chloro-2,3-epoxy-propane were stirred for 9 hours at a temperature of 90° C. The mixture was worked up according to example 5 (b) and 19.0 g 1-chloro-3-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-2-propanol was obtained (m.p. 104°-106° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH2:11][N:10]=2)[CH:4]=1.[CH3:23]OS(OC)(=O)=O>CC(C)=O>[CH3:23][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:8]=[CH:7][CH:6]=2)=[N:10][CH2:11][C:12]1=[O:20]
Reactant: O=C1CN=C(c2cccc(C(F)(F)F)c2)c2ccccc2N1
Reactant: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 15.2 g. of 1,3-dihydro-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one in 360ml. of acetone is treated with 7.5 ml. of dimethylsulfate and 45 g. of finely triturated, dry potassium carbonate and stirred intensively at room temperature for 15 hours. The mixture is then poured into 400 ml. of ice-water, the acetone is evaporated under reduced pressure and the separated oil extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. The resulting oil crystallizes on trituration with hexane, and there is obtained 1,3-dihydro-1-methyl-5-(α,α,α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one having a melting point of 117°-119° C., which can be employed in the next stage without further purification. A sample for analysis is obtained by crystallization from ethanol; melting point 121°-122° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)cn2)CC1
Yield: 99.9 %

Procedure:
Compound 32 (391 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10 mL), and 1-methylpiperazine (0.56 mL, 5.00 mmol) was added thereto, followed by stirring under heating and reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium chloride was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:1) to afford the entitled Compound 35 (454 mg, 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[N:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[N:34][CH:35]=4)[NH:32][CH:31]=[CH:30]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (224 mg, 0.61 mmol), (prepared as described for the starting material in Example 28), 5-hydroxy-7-azaindole (91 mg, 0.68 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (94 mg, 0.68 mmol) in DMA (5 ml) was stirred at 85° C. for 2 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (227 mg, 80%).
Reaction SMILES: N[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[BrH:10].N([O-])=O.[Na+].BrBr>O>[Br:10][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Br
Reactant: Cc1ccnc(Cl)c1N
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-amino-2-chloro-4-methylpyridine (2 g) was added to a mixed solvent of a 48% aqueous hydrogen bromide solution (17 mL) and water (12 mL). Sodium nitrite (2.5 g) was added to the solution at 0° C. Further, bromine (22 mL) was added. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was partitioned by adding a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.7 g).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].Cl[CH2:18][CH:19]=O>CC(C)=O>[S:3]1[CH:19]=[CH:18][N:2]=[C:1]1[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=CCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccs2)CC1
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-thiocarbamoylpiperidine-1-carboxylate (1 g, 4.09 mmol) in acetone (5 mL) was added 2-chloroacetaldehyde (0.32 g, 4.08 mmol). The mixture was heated under reflux for 4 hours. Additional 2-chloroacetaldehyde (0.32 g, 4.08 mmol) was added and heating was continued for another 14 hours. The solvent was removed by evaporation and the crude product was purified by silica gel chromatography to give tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate as an oil [530 mg (1.97 mmol); LC-MS=213.1 (M+H); 1H NMR (300 MHz, CDCl3) 7.74 (d, J=3.3 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 4.23 (brd, 2H), 3.22 (m, 1H), 2.91 (t, 2H), 2.14 (m, 2H), 1.77 (m, 2H), 1.48 (s, 9H)].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOC(C)=O>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:10]([CH2:9][CH2:8][O:7][C:6]1[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=1)[S:11]([CH3:14])(=[O:12])=[O:13])[CH3:30]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CS(=O)(=O)NCCOc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of NaH (60% in oil, 338 mg, 8.45 mmol) in DMF (23 mL) was cooled to 0° C. followed by addition of N-[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonamide (2.0 g, 7.04 mmol). The reaction was stirred at room temperature for 0.5 h and was cooled to 0° C. followed by addition of ethyl 7-bromoheptanoate (2.0 g, 8.45 mmol). The reaction was heated at 65° C. for 3 h and was cooled to room temperature. EtOAc was added and the organic solution was washed consecutively with 1N HCl, water, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (4:1 hexanes:EtOAc) provided the title compound (2.84 g). 1HNMR (400 MHz, CDCl3) δ6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56 (t, 2H), 3.22 (t, 2H), 2.86 (s, 3H), 2.26 (t, 2H), 1.60 (m, 4H), 1.32 (m, 4H), 1.22 (t, 3H).
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][O:12][CH2:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][O:12][CH2:11]2)[C:7]1=[O:18]
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCOC3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)COCO4
Yield: 57.9 %

Procedure:
To a solution of 310 mg (1.21 mmol) of 8H-5,9,11-trioxabenzo[de]anthracene-4,6-dione (from Example T3) in 4 mL pyridine was added 260 mg (3.74 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 2 hours and poured into 50 mL water while hot. The precipitate was isolated, washed with water, and dried to yield 190 mg of the title compound, mp 314-315° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[CH:32]=[CH:33][O:34]CC)CCC>C1(C)C=CC=CC=1.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>[CH3:24][O:23][C:10]1[CH:11]=[C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:4]=[C:3]([NH:25][CH3:26])[C:2]([C:33](=[O:34])[CH3:32])=[CH:7][N:6]=1
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1C(C)=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (100 mg, 0.24 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and tributylethoxyvinyltin (0.16 mL, 0.47 mmol) in toluene was stirred in a sealed tube at 110° C. for 1 hour. The reaction mix was filtered and concentrated. The reaction mixture was filtered through a pad of silica gel (eluted with 0-100% EtOAc in heptane) to give the crude product. Purification of the crude product was achieved by reverse phase HPLC (9 mg, 10%). Additional compounds made using the above procedure are shown in Table 4 above.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@@H:6]([CH2:7][OH:8])[C:5]1([CH3:21])[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1.[CH2:22](I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:21])[C:9]1[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:12]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: COCC1[C@@H](CO)C1(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: CCI
Product: CCOCC1[C@H](CO)C1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 77 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 39 but using Intermediate 38 as the starting material and ethyl iodide as alkylating reagent yielded the title compound (89 mg, 77% yield) as a colorless oil:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4](=[O:18])[CH2:3]1.[H-].[Na+].[C:21]([S:24][CH2:25]CBr)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([S:24][CH2:25][C:3]1([CH2:25][S:24][C:21](=[O:23])[CH3:22])[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[N:5]2[C:4]1=[O:18])(=[O:23])[CH3:22]
Reactant: CC(=O)SCCBr
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CC(=O)N12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SCC1(CSC(C)=O)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
(c) A solution of 1.27 g of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxyate in 10 ml of dimethylformamide was added to a suspension of 0.4 g of sodium hydride in dimethyformamide. The mixture was stirred at room temperature until the evolution of gas had ceased. 1.86 g of S-bromoethyl thioacetate were added and the mixture was heated at 75° C. for 5 hours. Working-up in the same manner as described in paragraph (D) (a) earlier gave 0.15 g (7%) of tert.butyl 2,2- bis(acetylthiomethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 85°-86° C. (from diethyl ether/hexane).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([OH:30])=O)[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:46][C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:30])[CH:25]([CH3:26])[CH3:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)C
Yield: 73.1 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (1 g) prepared by the method of Example 28 and L-phenylalanine (777 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-phenylalanine (900 mg) was obtained as powders according to a similar manner to that of Example 29.