Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:15].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:11][C:10](=[O:12])[CH2:9][C:6]1[C:5]2[CH:13]=[CH:14][C:2]([OH:1])=[C:3]([CH3:15])[C:4]=2[O:8][CH:7]=1
Reactant: Cc1c(O)ccc2c(CC(=O)O)coc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2c(C)c(O)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of (6-hydroxy-7-methyl-1-benzofuran-3-yl)acetic acid (2.61 g) in MeOH (80 mL) was added conc. H2SO4 (0.135 mL). The mixture was stirred at 60° C. for 1 h. The mixture was concentrated. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.52 g).
Reaction SMILES: [Na].[CH:2]([C:14]([O:16]CC)=O)([C:9]([O:11]CC)=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:19][C:20]([NH2:22])=[O:21]>C(O)C>[O:21]=[C:20]1[NH:22][C:9](=[O:11])[CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:14](=[O:16])[NH:19]1
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of anhydrous ethanol (1500 mL) was added sodium (25.2 g, 1.1 mol) in pieces. After all the sodium dissolved, triethyl ethane-1,1,2-tricarboxylate (180.0 g, 733 mmol) and urea (43.9 g, 733 mmol) was added respectively. The reaction mixture was heated at reflux overnight and cooled to room temperature, evaporated to dryness. The residue was diluted with water and acidified by diluted hydrochloric acid (2 N). The mixture was evaporated and purified by silica gel chromatography to afford the product ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate as a pale-yellow solid (82.8 g, yield 35.0%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1C(C)=[N+:13]([O-])[C:12]([C:17]#[N:18])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>>[C:5]([O:4][CH2:1][C:2]1[C:9]([CH3:8])=[CH:10][CH:11]=[C:12]([C:17]#[N:18])[N:13]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(C#N)[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCc1nc(C#N)ccc1C
Temperature: 120 °C
Yield: 67 %

Procedure:
To acetic anhydride (12 ml) at 120° C. was added 5,6-dimethyl-2-pyridine-carbonitrile 1-oxide (3.02 g) and the solution heated at 120° C. for 5 minutes then under reflux for 2.5 hours. After cooling the solution was added to ice (ca. 80 g) and the mixture neutralized with sodium bicarbonate. It was extracted with ether (80 ml then 2×40 ml) and the combined extracts washed with brine (40 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by Biotage chromatography eluting with 2:1 hexane:ethyl acetate to afford the title compound (2.60 g, 67%) as a pale yellow solid. LC/MS [MH+]=191, RT=2.05 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30]C)[O:7][C:8]1[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]2[C:16]=1[CH2:15][CH2:14][CH2:13]2)(=[O:3])[CH3:2].B(Cl)(Cl)Cl.C(O)C>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[OH:30])[O:7][C:8]1[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]2[C:16]=1[CH2:15][CH2:14][CH2:13]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(C(C)=O)c2)c2c1CCC2
Agent: ClB(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)=O)c2)c2c1CCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.6 %

Procedure:
To a solution of ethyl N-[7-(3-acetyl-4-methoxyphenoxy)-6-methylindan-4-yl]malonamate (268 mg) in dichloromethane (15 mL) was added a 1 mol/L solution of boron trichloride in dichloromethane (1.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. Ethanol was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (183 mg).
Reaction SMILES: [Br:1][CH:2]([C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)[C:3](=[O:12])[C:4]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[CH:6][CH:5]=1.CCOCC.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>C(Cl)(Cl)Cl>[Br-:1].[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]([CH:2]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][NH+:27]=2)[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: c1ccc2cnccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C(=O)C(c2ccc(OC)cc2)c2[nH+]ccc3ccccc23)cc1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A solution of α-bromodeoxy-p-anisoin (12 g) in isoquinoline (12 g) was heated in an oil bath at 160°0 for 10 minutes. The cooled reaction mixture was taken up in chloroform (50 ml), and the chloroform solution added dropwise, with stirring, to ether (600 ml). The suspension was stirred for 30 minutes, and the solid filtered off, washed well with ether and dried. Yield 18.0 g.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[O:7])=[CH:4][N:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:33]=[CH:34][C:2]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[N:3][CH:4]=3)=[O:7])=[C:11]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)[N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCCCC2)nc1
Temperature: 120 °C

Procedure:
In a 20 mL flask, 6-chloro-N-((7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide (Example I-6) (6 mg, 0.012 mmol) and piperidine (10.4 mg, 0.012 mL, 0.122 mmol) were combined with NMP (0.500 mL) to give a light yellow solution. The reaction mixture was heated at 120° C. for 1.5 hr. After this time, LC/MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, and the solvent was evaporated. The crude product was purified using preparatory reverse-phase HPLC. The product 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (d, J=2.30 Hz, 1H) 8.31 (d, J=8.59 Hz, 1H) 8.08 (br. s, 1H) 7.96 (d, J=0.80 Hz, 1H) 7.78-7.83 (m, 1H) 7.45-7.54 (m, 4H) 7.38 (d, J=8.20 Hz, 2H) 7.15 (d, J=0.80 Hz, 1H) 6.78-6.85 (m, 1H) 6.71 (d, J=1.95 Hz, 1H) 4.21 (d, J=4.69 Hz, 2H) 3.54-3.61 (m, 4H) 1.45-1.63 (m, 6H). MS calcd. for C30H26ClN5O3 [(M+H)+] 540.2, obsd. 540.1
Reaction SMILES: O.Cl[C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1.[I-:27].[Na+].Cl>C(#N)C>[I:27][C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: [I-]
Reactant: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 25 °C

Procedure:
A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (120 g, 346 mmol), as prepared above, sodium iodide (1.04 kg, 6.92 mmol), and 3 L of acetonitrile. To the yellow suspension is added concentrated hydrogen chloride (59.7 mL, 726 mmol) over 5 min. The white slurry is refluxed for 15 hours. The solvent is mostly removed by short-path distillation in vacuo. The resultant thick slurry is cooled to ambient temperature and treated with 2.5 L of water and 2.5 L of methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, concentrated and dried in vacuo at 30° C. yielding 7-iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2 --MeOH (1:1) gave an analytical sample as an off-white solid: 198-200° C. (dec.). 1H NMR (CDCl3, 200 MHz) d 2.30 (s, 3H), 2.43, 2.57 (m, 8H), 3.93 (s, 2H). 4.40 (s, 4H), 7.47 (s, 1H), 7.50 (s, 1H), 10.1 (s, 1H). Elemental analysis: Calculated for C18H20IN3O3 : C 47.70, H 4.45, N 9.27. Found: C 47.78, H 4.45, N 9.26.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[C:39]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-(methylsulfonyl)phenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O5S, 410.1; m/z found, 411.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.99 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.31-8.27 (m, 3H), 8.18 (d, J=8.5 Hz, 1H), 7.97 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 3.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[S:19][CH:20]=[C:21]([C:23]([O:25]CC)=O)[N:22]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]5[S:19][CH:20]=[C:21]([C:23]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:25])[N:22]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)n1
Reactant: C1CCNC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5nc(C(=O)N6CCCC6)cs5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 47 starting from ethyl 2-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydro isoquinolin-7-yl}-1,3-thiazole-4-carboxylate and pyrrolidine. LCMS (M+H)+: m/z=505.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(C)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
1-Methyl-piperazine (0.191 g, 1.91 mol) was added to a solution of Example 56k (0.5 g, 1.16 mmol) in dry DMF (10 mL) and stirred at 110° C. for 2 h. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.350 g, (60.97%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.5-2.60 (m, 10H, 5CH2), 2.70 (s, 3H, CH3), 3.10 (d, 2H, CH2), 3.90 (s, 3H, CH3), 5.10 (s, 2H, CH2), 6.7 (s, 2H, Ar), 8.01 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (ES+) 495 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH2:31])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[CH3:41]N.CO.C[O-].[Na+]>C1COCC1>[CH2:39]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=4[C:29]([NH:31][CH3:41])=[O:30])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:40]
Reactant: CN
Reactant: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(=O)NC)c4ccnc-4[nH]3)cc21
Reaction time: 48 h

Procedure:
The remaining half of the reaction mixture from the preparation of 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide was diluted with THF (100 mL) and a solution of methylamine (1M in THF, 10 mL). After 4 h the reaction mixture was concentrated, the resulting residue was sonicated in CH2Cl2 (10 mL) and filtered. The filtrate was purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2. The product was dissolved in THF (10 mL) and MeOH (20 mL) and treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The reaction mixture was stirred for 2 days, then concentrated onto Celite and purified by silica gel chromatography using 4% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a yellow solid (60 mg, 30% for 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, J=7.15 Hz, 6H) 2.58 (q, J=6.72 Hz, 4H) 2.80 (d, J=4.77 Hz, 3H), 3.12 (t, J=8.43 Hz, 2H),3.77 (s, 3H), 4.24 (t, J=8.43 Hz, 2H), 6.27 (dd, J=3.30, 1.83 Hz, 1H), 6.76-7.03 (m, 3H), 7.26-7.39 (m, 1H), 7.57 (s, 1H), 8.36 (d, J=8.43 Hz, 1H), 8.54 (s, 1H), 8.62 (s, 1H), 10.16 (s, 1H), 11.26 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=561.27.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].Br[C:16]1([C:20]([O:22]CC)=[O:21])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:16]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 65 °C

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (7 g, 0.03 mole), ethyl 1-bromocyclobutanecarboxylate (10.23 g, 0.049 mole) and potassium carbonate (7.5 g, 0.054 mole) in N,N-dimethylformamide (60 ml) was stirred and heated at 65° C. for 18 hours. The reaction mixture was poured into ice water and the resulting mixture was extracted with ether. The ether extract was washed with a 1% sodium hydroxide solution, then with water and finally dried over MgSO4. The ether was evaporated in vacuo and the residue treated with acetic acid (60 ml) and 5% hydrochloric acid (15 ml). The mixture was stirred and refluxed overnight. The solvents were evaporated in vacuo. The residue was chromatographed over a column containing silica gel (140 g) using methylene chloride/tetrahydrofuran/acetic acid 50/1/1 as the eluent. The pertinent fractions were united, treated with toluene and evaporated in vacuo to obtain 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid as a liquid whose identity was confirmed by NMR and purity by thin layer chromatography.
Reaction SMILES: Cl/[C:2](/[CH2:16][CH3:17])=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:42][C:43]([OH:47])(C)[C:44]#C>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[OH:47][C:43]([CH3:44])([CH3:42])[C:17]#[C:16]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: CC/C(Cl)=C\CN(CC)Cc1cccc(O)c1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
To 7.5 ml tetrahydrofuran were added 1.13 g (5 mmol) of (E)-N-(3-chloro-2-pentenyl)-N-ethyl-3-hydroxybenzylamine, 4.76 mg (0.25 mmol) of copper (I) iodide, 18.0 mg (0.1 mmol) of palladium chloride and 52.5 mg (0.2 mmol) of triphenylphosphine, and further, 0.99 ml (10 mmol) of n-butylamine and 0.58 ml (6 mmol) of 3-methyl-1-butyne-3-ol under ice cooling. The mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=3/2). The desired fractions were put together and concentrated under reduced pressure to obtain 1.07 g (yield: 78%) of the above identified compound as an oil.
Reaction SMILES: CN(C)[CH2:3][CH2:4][N:5](C)C.[Li]CCCC.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[2H][C:21]1([2H])[C:28](=O)[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[CH2:22]1>CCOCC.C1COCC1.Cl>[NH2:5][CH:4]([C:16]1[CH:15]=[CH:14][CH:19]=[CH:18][C:17]=1[C:28]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[CH2:22][CH:21]=1)[CH3:3]
Reactant: CCCCCC
Reactant: CN(C)CCN(C)C
Reactant: [2H]C1([2H])Cc2ccsc2C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)c1ccccc1C1=CCc2ccsc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound of Example 8 (7.3 g, 20.3 mmol) and N,N,N',N'-tetramethylethylenediamine (1.65 mL, 10.9 mmol) in dry ether (120 ml) was cooled to 0° C. and treated with a solution of n-BuLi (2.5M) in hexane (17.5 mL, 43.8 mmol). The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for an additional 1.5 hours. At this point the mixture was cooled to -78° C. A precooled solution of the compound of Example 5 (2.63 g, 18.8 mmol) in dry THF was then added by direct transfer via canula and the resulting mixture was stirred at -78° to -60° C. over 0.5 hour. The reaction was quenched by addition of saturated NH4Cl solution (40 mL) and was allowed to warm to room temperature. The mixture was diluted with ether and H2O. The ether layer was separated and concentrated to leave an oil which was taken up in a mixture of 1N HCl (200 mL) and THF (250 mL). The resulting solution was stirred at room temperature overnight. Following removal of most of the THF in vacuo, the solution was extracted twice with ether. The extracts were set aside for later recovery of unreacted compound of Example 5 while the aqueous layer was made basic by addition of solid NaOH and extracted twice again with ether. These extracts were combined, dried (Na2SO4) and concentrated in vacuo to leave a red oil. This was placed under high vacuum, warmed to remove α-methyl-benzenemethanamine and subjected to flash chromatography on silica gel. The column was initially eluted with CHCl3 to remove unwanted non-polar impurities. Subsequent elution with 2% and then 5% MeOH/CHCl3 provided, after removal of the solvents, the title compound (1.19 g, 26%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:22]([NH:21][C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[CH3:24])=[S:23])[CH3:2]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=S)Nc1cc(Cl)ccc1C)c1ccccc1
Yield: 94.9 %

Procedure:
A mixture of N-phenyl glycine ethyl ester (8.95 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), and chloroform (200 mL) was heated at reflux for 24 hours. The solvent was evaporated. The residue was crystallized from ethyl acetate/hexane mixture. The solid was collected and dried to give 17.2 g of 2-[3-(5-chloro-2-methylphenyl)-1-phenyl -thioureido]-acetic acid ethyl ester as a white solid, m.p. 148°-150° C. Anal. Calcd. for. C18H19Cl N2O S: C, 59.58; H, 5.28; N, 7.72. Found: C, 59.79; H, 5.38; N, 7.65. Mass spectrum (EI, M.+) m/z 262/264.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)C>[Cl:1][C:2]([Cl:11])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: Cc1ccccc1C=C(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)(Cl)Cl
Product: ClC(Cl)=Cc1ccccc1CBr

Procedure:
211 g (1.13 moles) of 2-(2,2-dichlorovinyl)-toluene, 251 g (1.41 moles) of N-bromosuccinimide and 2 g of azoisobutyronitrile in 1300 ml of dry 1,1,1-trichloroethane are refluxed, an additional 1 g of azoisobutyronitrile is added to the reaction mixture after one hour, and heating is continued for a further hour.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.[OH-:22].[Na+].Cl>C(O)C.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH2:20][CH:1]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])[CH2:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[O:22])=[CH:15][CH:14]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(C(CC(=O)c2ccc(F)cc2)CC(=O)c2ccc(F)cc2)c1
Yield: 55.1 %

Procedure:
A solution of 3-formylbenzoic acid (1 g, 6.66 mmol), 4'-fluoroacetophenone (1.21 g, 16 mmol), and sodium hydroxide (0.66 g, 16 mmol) in 60 mL of ethanol/water (1:1) is stirred at room temperature for 3 days. The reaction mixture is acidified with concentrated hydrochloric acid, and the resulting solid is collected by filtration. Recrystallization in hot chloroform provides 1.5 g of the title compound; mp 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[I:8].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH2:9][Br:10]
Reactant: Cc1ccc(I)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1I

Procedure:
A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisisobutyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state.