Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2C=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1.[NH2:22][NH2:23]>>[NH:22]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([Cl:20])[CH:18]=2)[N:3]=1)[NH2:23]
Reactant: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1Cl
Reactant: NN
Product: CCOC(=O)c1cnc(-c2ccc(Cl)c(Cl)c2)nc1NN
Yield: 99 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A mixture of N-(1-(3-bromophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (1.25 g, 3.7 mmol), tert-butyl piperazine-1-carboxylate (0.7 g, 3.7 mmol), diisopropylethylamine (1.0 mL, 5.7 mmol) and acetonitrile (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10%-15% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.45 g, 24%). 1H NMR (400 MHz, CDCl3): δ 8.72 (d, 1 H), 8.10 (d, 1H), 7.51 (s, 1H), 7.40 (m, 1H), 7.24 (m, 2H), 6.17 (dd, 1H), 5.60 (d, 1H), 4.52 (m, 1H), 3.48 (m, 4H), 3.26 (m, 2H), 3.13 (m, 2H), 1.63 (d, 3H), 1.44 (s, 9H). MS (ESI) m/z: Calculated: 504; Observed: 505 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH:44]=[CH:45][C:46](O)=O>CN(C)C=O>[CH2:9]([N:6]1[C:7]2[N:8]=[C:46](/[CH:45]=[CH:44]/[C:43]3[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:41]([O:40][CH3:39])[CH:42]=3)[NH:1][C:2]=2[C:3](=[O:13])[NH:4][C:5]1=[O:12])[CH2:10][CH3:11]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)c(OC)c3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
5,6-Diamino-1-propyluracil (2.00 g, 11 mmol) was suspended in 40 ml of N,N-dimethylformamide. To the suspension were added 3.37 g (16 mmol) of N,N'-dicyclohexylcarbodiimide and 2.00 g (13 mmol) of 1-hydroxybenzotriazole. Then, 2.59 g (11 mmol) of 3,4,5-trimethoxycinnamic acid was slowly added thereto in several portions, and the mixture was stirred overnight at room temperature. After insoluble substances were removed by filtration, the filtrate was concentrated under reduced pressure and 40 ml of a 2N aqueous solution of sodium hydroxide was added to the residue. The mixture was heated under reflux for 30 minutes, followed by neutralization. Deposited crystals were collected by filtration and recrystallized from isopropanol/water to give 2.51 g (overall yield: 60%) of Compound 22 as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:45](B1OC(C)(C)C(C)(C)O1)=[CH2:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:41]([O:40][C:38]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:45]=[CH2:46])[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccnn2C2CCCCO2)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(-c2ccnn2C2CCCCO2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-trifluoromethanesulfonyloxybenzoate (Intermediate 11, 4.35 g), vinylboronic acid pinacol ester (1.9 mL), bis(triphenylphosphine)palladium (II) dichloride (0.255 g) and cesium carbonate (7.1 g) in dioxane (300 mL) and water (47 mL) was de-gassed and purged with nitrogen. The mixture was then heated to 80° C. for 4 hours. After cooling, the mixture was diluted with ether and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-vinylbenzoate (2.84 g) as a gum.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:6][C:5]([SH:12])=[C:4]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:3]=1.Br[C:18]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:18][S:12][C:5]1[CH:6]=[C:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[CH:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Reactant: CCC(C)c1cc(Br)c(C(C)CC)cc1S
Product: CCC(C)c1cc(SC)c(C(C)CC)cc1Br

Procedure:
4-Bromo-2,5-di-sec-butylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-bromo-2,5-di-sec-butylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 126°C at 0.3 mm Hg.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:27]([CH3:29])[CH3:28])[C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.C(C1C2OCC(C)(C)C=2C=C(NC(C)C)C=1)(C)(C)C.[OH-].[K+]>C(O)C>[CH:27]([N:11]([C:12]1[CH:13]=[C:14]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:15]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(N(c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Agent: CC(C)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Yield: 3.7 %

Procedure:
Following general procedure H and using 4-[isopropyl-(7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 40, 0.1 5 g contaminated with 67% of 5-(isopropyl)amino-7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran (Compound 36) and 2.5 mL of 4M potassium hydroxide solution in 4 mL of ethanol, the title compound (0.034 g, 3.7% for 2 steps) was obtained. 1H NMR (300 MHz, CDCl3): δ 7.86(d, 2H, J=9.0 Hz), 6.75 (d, 1H, J=2.1 Hz), 6.66 (d, 1H, J=2.1 Hz), 6.51 (d, 2H, J=9.1 Hz), 4.36 (heptet, 1H, J=6.5 Hz), 4.28 (s, 2H), 1.34 (s, 9H), 1.32(s, 6H), 1.15 (d, 6H, J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]([CH3:19])[CH2:17][OH:18])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:18][CH2:17][CH:16]([C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH:13]([CH3:15])[CH3:14])[CH3:19])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of 2-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propan-1-ol (225 mg, 0.694 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (190 mg, 0.972 mmol) in toluene (15 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (224 mg, 1.11 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (280 mg, 1.11 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded directly on silica gel column chromatography with 10–15% EtOAc/Hexanes to afford the title compound (320 mg, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][C:4]=2[F:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), P(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (62%) of compound 78. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H), 4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d, J=16.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].O>O1CCOCC1>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Br:1])=[C:3]([O:24][CH3:25])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1csc(C(C)C)n1)CC3=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 60.9 %

Procedure:
A mixture of 15B (2.0 g, 4.7 mmol), FeCl3.6H2O (6 g) in 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15C (1.2 g, 60.2% yield).
Reaction SMILES: [F:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[C:8]([F:20])[CH:7]=[C:6]([N+:21]([O-])=O)[C:3]=1[NH:4][CH3:5]>[Ni].C1COCC1>[F:1][C:2]1[C:3]([NH:4][CH3:5])=[C:6]([CH:7]=[C:8]([F:20])[C:9]=1[N:10]1[CH2:11][CH2:12][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:15]1)[NH2:21]
Reactant: CNc1c([N+](=O)[O-])cc(F)c(N2CCC(C(F)(F)F)CC2)c1F
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1c(N)cc(F)c(N2CCC(C(F)(F)F)CC2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4-difluoro-N-methyl-6-nitro-3-(4-trifluoromethyl-piperidin-1-yl)aniline (210 mg, 0.62 mmol), Ra—Ni (4 mg, 0.062 mmol) and THF (30 mL) was shaken under H2 atmosphere (1 atm) at rt for 1 h. The mixture was filtered through celite and the celite pad was further washed with THF. The resulting solution was concentrated to give the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.[CH:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:14]2[CH2:15][CH2:16][C:13]=12)=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.C(#N)C>[CH:10]([CH:5]1[C:4]2=[CH:7][CH:8]=[CH:9][CH:2]=[C:3]2[CH2:6]1)=[CH2:11].[CH:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:14]2[CH2:15][CH2:16][C:13]=12)=[CH2:11]
Reactant: Brc1cccc2c1CC2
Agent: [Pd+2]
Agent: C=C
Agent: C=Cc1cccc2c1CC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CC1Cc2ccccc21
Temperature: 125 °C
Reaction time: 16 h

Procedure:
The monomer is prepared by heating a mixture of 4-bromobenzocyclobutene with 4-vinylbenzocyclobutene at reflux. Vinylbenzocyclobutene is prepared by adding 0.98 g of 4-bromobenzocyclobutene, 0.04 g palladium (II) acetate, and 0.17 g of tri-o-tolylphosphine to a mixture of 100 ml acetonitrile and 0.6 g of triethylamine in a 450 ml Parr pressure reactor. The reactor is pressurized with 250 psig ethylene. The mixture is heated to 125° C. and stirred for 16 hours. The apparatus is cooled and the remaining ethylene is vented. The product is washed with water and 5 percent hydrochloric acid and dried over MgSO4. The solvent is removed to provide 4-vinylbenzocyclobutene. A 2.4 g sample of 4-bromobenzocyclobutene, a 1.7 g of 4-vinylbenzocyclobutene, a 2.4 g of tri-n-butylamine, a 100 mg of tri-o-tolylphosphine, 29 mg palladium (II) acetate and 10 ml acetonitrile are added to a fask equipped with a reflux condenser, nitrogen inlet, and magnetic stirrer. The reaction mixture is heated to reflux under nitrogen for 4 hours. The solution is cooled to room temperature and stirred into 60 ml of 10 percent hydrochloric acid solution. The precipitate is collected by filtration, washed with water and air dried. The product is recrystallized from ethylacetate and has a melting point of 132° to 133° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2F)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[Mg].II.[C:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>CCOCC.II>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:13]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)([OH:15])[CH3:14]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of 1-bromo-2-(bromomethyl)benzene (4.40 g, 17.60 mmol), magnesium (0.984 g, 40.5 mmol), and I2 (2.2 mg, 8.80 μmol) in Et2O (87 mL) was heated to reflux under argon until the reaction initiated (indicated by decolorization of I2) and then stirred at room temperature for 2 hours. After this time, the reaction mixture was added to a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (2 g, 8.80 mmol) in Et2O (1.2 mL) and then stirred for 19 hours. At the conclusion of this period, the reaction mixture was quenched with aqueous NH4Cl (saturated, 20 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with H2O (3×15 mL) and brine (15 mL). The resulted organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 11A as a white semi-solid (1.14 g, 31% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:40][CH2:39][CH:38]([N:35]5[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]5)[CH2:43][CH2:42]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 105 °C
Yield: 66.3 %

Procedure:
Following the procedure of Example 11, a mixture of 110 mg (0.25 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 140 mg (0.76 mmol) of 1-methyl-4-piperidin-4-ylpiperazine in 0.8 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 28 hours to yield the crude product. Purification by silica gel chromatography (gradient 94:6 methylene chloride/methanol to 84:15:1 methylene chloride/methanol/ammonium hydroxide) gives 100 mg of the 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinoline-3-carbonitrile as a beige solid, mp 235-237° C.
Reaction SMILES: O.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:17](Br)=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[N:21][CH:20]=[CH:19]3)[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33]([B-](F)(F)F)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([C:17]1[C:16]([O:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Cc2c(OC3CCNCC3)ccc3cnccc23)cc1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
0.3 mL of water were added to a solution of 81 mg (0.2 mmol) of 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11), 195 mg (0.6 mmol) of Cs2CO3, 14.6 mg (0.02 mmol) of Pd(dppf)Cl2 and 51 mg (0.26 mmol) of potassium benzyltrifluoroborate in 3 mL of THF. Argon was bubbled through the mixture for 10 minutes and then the reaction was heated to reflux for 16 h (incomplete conversion). After cooling to room temperature water and ethyl acetate were added. The organic layer was separated, dried over Na2SO4. After removal of the solvents 2 mL 5-6 N HCl in isopropanol was added. After 2 h the solvents were distilled off and the remainder was subjected twice to preparative HPLC to give 3.5 mg compound 29 as trifluoroacetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C[P+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCBr
Agent: C[P+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
A mixture of 0.53 g of 3-bromopropanol, 5.0 g of toluene and 0.06 g of trimethylphenylphosphonium bromide was heated to 60° C. Thereto was added dropwise a mixed solution of 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of water and 0.54 g of a 27% aqueous sodium hydroxide solution with stirring over 6 hours. After completion of the addition, the mixture was further stirred at 60° C. for 4 hours. Then 0.10 g of 3-bromopropanol and 0.10 g of a 27% aqueous sodium hydroxide solution were added thereto, and the mixture was further stirred for 7 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution and 5.0 g of toluene were added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 90%, yield: 91%).
Reaction SMILES: N.[C:2]1([CH:8]([CH3:10])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:11]>>[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: O
Reactant: CC(C)c1ccccc1
Agent: N
Product: CC(=O)c1ccccc1

Procedure:
Binary Azeotrope: A water borne solution of SMA ammonia adducts (25% solid) was heated. At 93° C., a binary azeotrope mixture of cumene and acetophenone was formed that carried cumene and acetophenone out of the resin solution. After keeping the solution at 93° C. for six hours, the level of acetophenone was reduced to 2% (a 98% reduction) and the level of cumene was reduced to 25% (a 75% reduction) of their original levels. An azeotrope can also be formed under reduced pressure. Similar results in the reduction of cumene and acetophenone levels were obtained under reduced pressure (0.15 atmosphere) at 93° C. and four hours.