Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2].[Br-].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][Zn+]>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.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21]([CH2:36][C:35]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=4[F:33])=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:27])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2CCN(c3nnc(Cc4ccc(F)cc4F)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 2-[(R)-4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (229 mg, 0.50 mmol, 1 eq) and THF (1.4 mL) in a microwave vial is added 2,4-difluorobenzylzinc bromide (2.0 mL 0.5 M solution in THF, 2.0 mmol, 4 eq) and tetrakis(triphenylphosphine)palladium (25 mg, 0.03 mmol, 0.05 eq). The vial is sealed and heated in the microwave at 60° C. (high absorption setting) for 25 min. An additional aliquot of 2,4-diflorobenzylzinc bromide (1.0 mL 0.5 M solution in THF, 1.0 mmol, 2 eq) is added and the reaction mixture is heated in the microwave at 100° C. (high absorption setting) for 5 min. The reaction mixture is quenched with water (10 mL) and then extracted with EtOAc (2×25 mL). The combined organic fractions are dried over magnesium sulfate, concentrated and purified by silica gel chromatography (25-75% EtOAc/Heptane) to yield the desired compound (225 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 71 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 90%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 12.9 g (0.112 mol) of N-hydroxysuccinimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 23.4 g of the target compound was obtained as a pale yellow oily substance (yield: 56%, purity: 79%, pure content: 18.5 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([CH:9]=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CO)n1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1csc(C=O)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.8 %

Procedure:
(4-Isopropyl-1,3-thiazol-2-yl)methanol (5.20 g, 33.0 mmol) was dissolved in methylene chloride (100 ml), added with pyridinium dichromate (14.9 g, 39.7 mmol), and stirred at room temperature for 19 hours stirred. After insoluble solids were removed, the reaction solution was evaporated, and the residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (3.32 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(C=O)c3ccccc23)cc1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Temperature: 195 °C
Yield: 104.4 %

Procedure:
To a 35 ml flask was added 4-(3-fluoro-4-methoxyphenyl)-naphthalene-1-carbaldehyde (720 mg ˜80% pure, 2.05 mmol), and pyridine hydrochloride (3 g, 26 mmol). The mixture was warmed to 195° C. for 2 h, cooled slightly, and the remaining pyridine hydrochloride was dissolved in water (50 ml). The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous Na2SO4, passed through a silica plug and concentrated to afford 570 mg (99%) of product as an off-white foam. The material was carried on to the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 7.16 (2H, m), 7.35 (1H, d, J=12.00 Hz), 7.60–7.80 (3H, m), 7.98 (2H, d, J=8.3 Hz) 8.22 (1H, d, J=7.4 Hz), 9.28 (1H, d, J=8.4), 10.24 (1H, s), 10.43 (1H, s).
Reaction SMILES: [CH2:1]([N:8]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=1Br)[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH2:1]([N:8]1[C:14]2[C:15](=[CH:16][C:17]([CH3:22])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:10]([CH3:12])([CH3:11])[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N(Cc2ccccc2)C(=O)C(C)C)c(Br)cc1C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1C)C(C)(C)C(=O)N2Cc1ccccc1
Yield: 56.8 %

Procedure:
To a solution of N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (4.35 g, 11.56 mmol) in 1,4-dioxane (115 mL) was added sodium tert-butoxide (1.66 g, 17.34 mmol). The mixture was degassed under argon for 30 minutes, then palladium (II) acetate (130 mg, 0.58 mmol) and tricyclohexylphosphine (162 mg, 0.58 mmol) were added and the mixture refluxed overnight. A solution of saturated aqueous ammonium chloride was added and the solution extracted with ethyl acetate. The organic extract was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 1.94 g of 1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (57% yield). 1H NMR (300 MHz; CDCl3): 1.40 (s, 6 H), 2.16 (s, 3 H), 3.67 (s, 3 H), 4.90 (s, 2 H), 6.26 (s, 1 H), 6.96 (s, 1 H), 7.27 (m, 5 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN1CCCCC1
Solvent: C1COCCO1
Product: Clc1ccnc(N2CCCCC2)n1
Yield: 10.9 %

Procedure:
These intermediates were prepared following a procedure by K. Yoshida et al, J. Chem. Soc. Perkins Transactions I., (1992), 919-922. A solution of 2,4-dichloropyrimidine (4.00 g, 26.8 mmol) and 1-methyl-piperidine (3.25 mL, 29.5 mmol) in 1,4-dioxane (60 mL) was stirred at 100° C. for 3 d, then cooled and evaporated. Purification by flash chromatography (SiO2) eluted with 15:85 ethyl acetate: hexanes provided 4-chloro-2-piperidin-1-yl-pyrimidine (0.58 g, 12% yield) as a pale yellow solid: 1H-NMR (CDCl3, 500 MHz) 8.06 (d, 1H), 6.37 (d, 1H), 3.70 (m, 4H), 1.61 (m, 2H), 1.53 (m, 4H) ppm; MS (FIA) 198.1 (M+H); HPLC (method A) 3.550 min. and 2-chloro-4-piperidin-1-yl-pyrimidine (1.87 g, 38% yield) as a white solid: 1H-NMR (CDCl3, 500 MHz) 8.01 (d, 1H), 6.41 (d, 1H), 3.65 (m, 4H), 1.73 (m, 2H), 1.65 (m, 4H) ppm; MS (FIA) 198 (M+H); HPLC (method A) 2.583 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:15].[CH2:16](O)[CH3:17]>>[ClH:15].[CH2:16]([O:13][C:12](=[O:14])[C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:11])[CH3:17]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of O-benzyl-L-serine (9.75 g, 50 mmol) in ethanol (200 mL) is saturated with HCl gas for 8 minutes. The mixture is stirred overnight at room temperature, and then concentrated in vacuo. The solid is washed with diethyl ether and collected by filtration to yield O-benzyl-L-serine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37]OC)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[O-2].[Al+3].[O-2].[O-2].[Al+3].C(Cl)Cl.[CH2:48](O)[CH3:49]>>[CH2:36]([O:35][C:30]1[C:8]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=2[C:33]([CH3:34])=[CH:32][CH:31]=1)[CH2:37][CH2:48][CH3:49]
Reactant: CCCCc1nc2c(C)ccc(OCCOC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCO
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1ccc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c12

Procedure:
tert.butyl 4'-[(2-n-butyl-7-(2-methoxyethoxy)-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Aluminium oxide plate: methylene chloride/ethanol=99:1)
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[NH:4][C@@H:5]([CH3:8])[CH2:6][OH:7].C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.CC(C)=O>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[N:4]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:5]([CH3:8])[CH2:6][OH:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 61.6 %

Procedure:
The compound (300 mg) obtained in Example 51, diethyl ethoxymethylenemalonate (632 mg) and tetrahexylammonium chloride (57 mg) were dissolved in acetone (3 ml). After adding potassium carbonate (445 mg), the mixture was stirred at room temperature for 4.5 hours. After the completion of the reaction, the solvent was evaporated. Then the residue thus obtained was subjected to silica gel column chromatography to thereby give 338 mg (84%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[CH2:15]([NH:19][C:20](=[O:56])[C@H:21]([CH3:55])[CH2:22][C@H:23]([OH:54])[C@@H:24]([NH:46]C(OC(C)(C)C)=O)[CH2:25][C:26]([CH3:45])([CH3:44])[CH2:27][C:28](N1C2C(=CC=CC=2)CC(NC(C)=O)C1)=[O:29])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:20](=[O:56])[C@H:21]([CH3:55])[CH2:22][C@H:23]([OH:54])[C@@H:24]([NH2:46])[CH2:25][C:26]([CH3:44])([CH3:45])[CH2:27][C:28]([N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:29])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)C1COc2ccccc2N1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(C)=O)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1c2ccccc2OCC1C(=O)OC

Procedure:
Starting from 78 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-3(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 80)) in a manner analogous to that described in Example 1): Rf (S)=0.37; FAB-MS: (M+H)+ =492.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:34]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:15]3=[N:16][CH:17]=[C:18]([Cl:33])[C:19]([C:20]4[S:24][C:23]([C:25]5([O:29]COC)[CH2:28][CH2:27][CH2:26]5)=[N:22][CH:21]=4)=[C:14]3[CH:13]=2)[CH:9]=[N:8]1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3C=NN(CCN4CCOCC4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:34]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[C:15]3=[N:16][CH:17]=[C:18]([Cl:33])[C:19]([C:20]4[S:24][C:23]([C:25]5([OH:29])[CH2:28][CH2:27][CH2:26]5)=[N:22][CH:21]=4)=[C:14]3[CH:13]=2)[CH:9]=[N:8]1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC5OCCO5)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN5CCOCC5)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CC4OCCO4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1

Procedure:
The title compound was prepared as described in Example 1H, substituting 5-(2-(1-(1,3-dioxolan-2-yl)methyl)-1H-pyrazol-4-yl)-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 13A) for 4-(2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (Example 1G). MS ESI(+) m/z 612.1 [M+H]+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1)=O.[OH-].[Na+].O>C(O)C>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1
Reactant: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C(F)(F)F)cn3c2)c1)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.8 %

Procedure:
To a solution of N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (400 mg, 0.787 mmol) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→80/20), and fractions containing the desired product were concentrated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether (1:4) to give the title compound (350 mg, quantitative) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2cccc(OCc3ccccc3)c2C(=O)c2c(Cl)ccc(Cl)c21
Yield: 86.8 %

Procedure:
A mechanically stirred mixture of 177.2 g (0.605 mol) of 1,4-dichloro-5-hydroxy-9,10-anthracenedione (1, British Pat. No. 1,029,448), 83.5 g (0.605 mol) of powdered anhydrous potassium carbonate, 79 ml (0.675 mol) of benzyl bromide, and 1.7 l of dry acetone was heated at reflux for three days. The initial dark brown suspension changed to an olive green color signaling the end of the reaction. The mixture was filtered hot and the salts were washed with hot acetone. The cooled filtrate was concentrated to ~1/2 of its volume. The yellow precipitate was collected by filtration, washed with acetone and methanol, and dried at 200 mm/50° C./12 hr to leave 201.2 g (87%) of 2, mp 122°-126° C.
Reaction SMILES: [CH2:1]([S:13][CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC[OH:30]>CO.O>[CH2:1]([S:13]([CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:24])([CH3:25])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCO
Reactant: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCS(=O)C(C)CC(=O)C1C(C)C=CCC1(C)C
Reaction time: 15 h
Yield: 38 %

Procedure:
A solution of 3-(dodecylthio)-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (2.00 g; 5.10 mmol) in MeOH (20 ml) was added at 0° C. to a solution of NaIO4 (1.14 g, 5.30 mmol) in H2O (11 ml). The temperature was brought to room temperature and EtOH (30 ml) was added. The suspension was stirred for 15 h and title compound extracted (ether/brine). The organic phase was washed with aqueous NaHSO3, H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated. (16.2 g). Flash chromatography (cyclohexane/ethyl acetate=7:3, then 1:1) on SiO2 (40 g) afforded 803 mg of the title compound (38%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>O1CCOCC1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: BrCCCCCCOCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride in 1,4-dioxane was added benzyl alcohol in 1,4-dioxane over a period of 30 minutes at 80° C., and the mixture was stirred for 1 hour. The obtained alkoxide solution was added to a solution of 1,6-dibromohexane in 1,4-dioxane at room temperature. The mixture was stirred at 80° C. for 14 hours and insoluble materials were filtered off. The filtrate was concentrated and the residue was distilled under reduced pressure to give the object compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH2:51])=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:46])([F:45])[F:44])(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH:51][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:44])([F:45])[F:46])(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(C(=O)NNC(=O)CN(Cc2ccccc2)S(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a stirred solution of 3-methylsulfonylbenzoic acid (60 mg) in N,N-dimethylacetamide (1.3 mL) was added 1,1′-carbonyl-diimidazole (52 mg). The mixture was stirred at 50° C. for 20 min. After cooling to r.t., N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (100 mg) was added and the mixture was stirred at 100° C. overnight. After cooling to r.t. the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, dichloromethane to dichloromethane/methanol 95:5) to give N-benzyl-N-{2-[N′-(3-methanesulfonyl-benzoyl)-hydrazino]-2-oxo-ethyl}-2-trifluoromethyl-benzenesulfonamide (111 mg) as a colorless oil. MS: 570.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cc(Cl)c(Cl)cc1F
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
In one particular, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline. Then, the 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline is reacted with a carbon-11 labeled acryloyl chloride so as to produce a carbon-11 labeled {4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl]acrylamide (radiolabeled Compound 3).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClC(OCCCC)=O.Cl.C(N(CC)CC)C.Cl.[CH3:40][O:41][C:42](=[O:53])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)[NH2:44].Cl>C(#N)C.CO.C(N(CC)CC)C>[CH3:40][O:41][C:42](=[O:53])[C@H:43]([CH2:45][C:46]1[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][CH:51]=1)[NH:44][C:1](=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Arachidonic acid (152 g, 0.5 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in 3 ml of dry acetonitrile and chilled to −15° C., and 70 mg (0.51 mmol) of butyl chloroformate was added. After 30 min, the mixture free of the precipitated triethylamine hydrochloride was pipetted in a solution of tyrosine methyl ester hydrochloride (232 mg, 1 mmol) and 0.14 ml of triethylamine in 1 ml of methanol, stirring was continued for 15 min at −15° C., then the mixture obtained was allowed to want to room temperature. After 2 h, 0.5 M HCl was added, and the mixture was extracted with ether (20 ml). The extract was washed with water, then dried with Na2SO4, and evaporated in vacuo. The residue was dissolved in 2 ml of chloroform and purified by column (2×2 cm) chromatography on aluminum oxide (basic, Brockmann II). Elution of the column with chloroform-methanol (9:1 v/v) and evaporation of the appropriate fractions gave 222 mg (95%) of desired N-arachidonoyl-L-tyrosine methyl ester as oil: TLC (system A) Rf 0.6.