Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:17][C:18]1[C:22]([CH3:23])=[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[S:20][C:19]=1[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].C(Cl)[Cl:49]>>[ClH:49].[ClH:49].[ClH:49].[N:33]1[CH:34]=[CH:35][C:30]([C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[C:22]([CH3:23])[C:18]=2[CH2:17][NH:8][OH:9])=[CH:31][CH:32]=1
Reactant: ClCCl
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CNO
Product: Cl
Reaction time: 2 h

Procedure:
To a stirred solution of N,O-di-tert-butoxycarbonyl-[2,5-di(4-pyridyl)-4-methylthiophen-3-yl]methylhydroxylamine (0.16 g) in CH2Cl2 (15 mL) was added trifluoroacetic acid (0.5 mL) and the mixture watered for 2 hours at room temperature. Trifluoroacetic acid (3 mL) was additionally added to the reaction mixture, and stirred for 2 hours. Saturated aqueous NaHCO3 solution was added to the reaction mixture and the whole was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2 (1:1). The crude product was dissolved in 10% methanolic HCl (1 mL) and the volatiles were removed by evaporation. The resulting solid was recrystallized from diisopropyl ether to give the title compound (0.031 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)=[CH:27][C:17]=1[CH2:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][N:19]([CH2:18][C:17]2[CH:27]=[C:28]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)[CH:29]=[CH:30][C:16]=2[F:15])[CH:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCC(NCc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N(Cc2ccc(F)cc2)Cc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Sodium triacetoxyborohydride (470 mg, 2.23 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of [2-fluoro-5-(1H-indol-5-yl)-benzyl]-(1-methyl-piperidin-4-yl)-amine (250 mg, 0.74 mmol) and 4-fluorobenzaldehyde (183 mg, 1.48 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with the careful addition of saturated sodium bicarbonate solution. The organic phase was separated and dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/ethyl acetate) provided 232 mg of product. LC/MS (long run): Retention time, 6.12 min; (M+H)=446.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br-:20]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:20][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Yield: 90.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-(4-nitro-phenyl)-1-phenyl-propan-1-one prepared in the step and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 90.4%, mp: 97-98 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.48 (1H, dd, J=14.28, 7.28 Hz), 3.75 (1H, dd, J=14.28, 7.28 Hz), 5.31 (1H, t, J=7.28 Hz, CHBr), 7.46˜7.51 (4H, m, ArH), 7.61 (1H, t, J=8.00 Hz, ArH), 7.98 (2H, d, J=8.68 Hz, ArH), 8.17 (2H, d, J=8.68 Hz, ArH); FAB-MS: 336.1 (M+2, 90), 334.1 (M, 90), 254.2 (58), 238.2 (36), 105.1 (100).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[C:23]1([S:29]([CH2:32][CH2:33][NH:34][CH:35]([CH3:37])[CH3:36])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:36][CH:35]([N:34]([CH2:33][CH2:32][S:29]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:30])=[O:31])[C:1]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:2])[CH3:37]
Reactant: NCCCN1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(CCS(=O)(=O)c1ccccc1)C(=O)NCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
A mixture of 5.16 g (0.0319 mole) of 1,1'-carbonyldiimidazole and 4.16 g (0.029 mole) of N-(3-aminopropyl)piperidine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 6.13 g (0.027 mole) of N-[2-(phenylsulfonyl)ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed for 20 hr. The solvent was removed in vacuo, and the residue was dissolved in a 60/40 mixture of ether and methylene chloride, respectively. The solution was extracted with three portions of water and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. Flash chromatography on silica gel (chloroform and methanol, gradiently eluted with methanol up to 10% methanol) gave 2.89 g (27.1%) of oil: 1H NMR (CDCl3)δ7.4-8.03 (m, 5, aromatic), 6.4 (br s, 1, NH) 3.88 (m. 1, (CH3)2 (H), 3.44 (s, 4, SO2CH2CH2, 2.33 (br q, 2 NHCH2), 2.2-2.5 (m. 6. CH2CH2CH2N, and 2, 6-piperidine H), 1.3-1.83 (m, 8, (CH2CH2CH2N, and 3, 4, 5-piperidine H), 1.1 (d, 6, (CH3)2CH).
Reaction SMILES: [C:1]1([CH:7]2[N:11]([CH:12]([CH3:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]([CH2:22][OH:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([OH:8])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[C:1]1([CH:7]2[N:11]([CH:12]([CH3:21])[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH:9]([CH2:22][OH:23])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 95 (7.6 g, 0.025 mol) in pyridine (15 ml) was cooled in an ice bath and p-toluenesulfonyl chloride (4.7 g, 0.025 mol) was added while keeping the internal temperature below 30° C. After stirring for 3 hours at room temperature, a saturated solution of Na2CO3 was added and the mixture extracted with CH2Cl2 (3X). The organic extracts were dried, filtered and concentrated under reduced pressure below 50° C. initially using water aspirator pressure and finally high vacuum to yield the p-toluene sulfonate of 95 (0.025 mol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1>[Cu]>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])=[CH:10][C:11]=1[F:16]
Reactant: Nc1ccc(Br)cc1F
Reactant: Oc1ccccn1
Agent: [Cu]
Product: Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
The process described in patent US2005/0215599, i.e. copper catalyzed N-arylation of 2-hydroxypyridine with 4-bromo-2-fluoroaniline suffers from a major safety issue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]5[C:29](=[O:37])[C:30](=[O:36])[C:31]=5[O:32]C(C)C)[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.Cl.O>CO>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]5[C:31](=[O:32])[C:30](=[O:36])[C:29]=5[OH:37])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(OC(C)C)c(=O)c4=O)cc23)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(O)c(=O)c4=O)cc23)CC1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5 [1,2-dioxo-4-(1-methylethoxy)-3-cyclobuten-3-yl]aminoindole (I-3) (0.175 g, 0.35 mmol) in 5 mL of methanol was added 0.10 mL (0.60 mmol) of 6N HCl and the mixture was heated at ca. 80° C. for 5 h. Another 0.10 mL (0.60 mmol) of 6N HCl was then added, as well as 0.20 mL of H2O, and the mixture was heated at ca. 100° C. for 18 h. On cooling to room temperature, the resulting suspension was filtered and the residue was washed (acetone, ether) and then air-dried. This solid (0.130 g) was taken up in methanol and the resulting solution was treated with charcoal, filtered and evaporated to give the hydrochloride salt of the title compound (0.075 g, 36%) as a beige solid, mp 215° C. (dec): IR (KBr) 3410 (br), 3240 (br), 1783, 1700, 1632, 1547 cm -1 ; 1H NMR (DMSO-d6, 200 MHz) δ10.88 (s, 1H), 10.37 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.62 (s, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J=8.6, 1.8 Hz, 1H), 4.80 (br m, 2H), 3.90 (s, 3H), 3.57 (br m, 4H), 3.13 (br m, 4H), 2.73 (m, 2H), 2.12 (m, 2H). Anal. Calcd for C24H26N6O4. 3 HCl. H2O: C, 48.86; H, 5.30; N, 14.25. Found: C, 48.81; H, 5.51; N, 14.22.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[O:21][CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
18.7 g of 1-acetylisonipecotoyl chloride, Example 1(b) are added slowly to a stirred mixture of 40.0 g of m-dimethoxybenzene and 19.2 g of aluminum chloride in 75 ml of carbon disulfide. The reaction mixture is stirred at ambient temperature for an hour, poured into ice-water and extracted with chloroform, the combined extracts are dried and the chloroform is removed, leaving a yellow oil. The oil is triturated with ether to give a white solid, which is recrystallized twice from ethyl acetate to give the pure solid, mp 132°-134° C., 1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1.N1CCCCC1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:7]3/[C:8](=[O:11])[NH:9][C:10]4[C:6]/3=[CH:5][CH:4]=[CH:3][C:2]=4[NH2:1])[CH:19]=2)[CH:14]=[N:13]1
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: Nc1cccc2c1NC(=O)/C2=C/c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 28 %

Procedure:
A 13 mg (0.0877 mmol) solution of 7-aminooxindole (T. Nakashima & I. Suzuki, Chem. Pharm. Bull. (1969) 11, 2293) and 1H-indazole-6-carbaldehyde (14 mg, 0.0965 mmol) in MeOH (1.0 mL) was treated with piperidine (˜1 uL, 0.00877 mmol) and the reaction was heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with 95:5 CH2Cl2/MeOH. The resulting precipitate was filtered and washed with 95:5 CH2Cl2/MeOH to obtain the title compound as a orange powder (6.7 mg, 28%). NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.94-7.87 (m, 3H), 7.46 (d, J=8.19 Hz, 1H), 7.31 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.89 Hz, 1H), 6.81 (t, J=7.79 Hz, 1H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.11.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(O[Si](C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(C)(C)O[Si](C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 51.5 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M Na2CO3 solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 16-(1); 26.3 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17](I)([C:20]([C:23]([C:26]([C:29]([C:32]([F:35])([F:34])[F:33])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18]>CS(C)=O.[Cu]>[F:18][C:17]([F:19])([C:2]1[C:3]2[C:8]([C:9]([C:17]([F:19])([F:18])[C:20]([F:21])([F:22])[C:23]([F:24])([F:25])[C:26]([F:27])([F:28])[C:29]([F:31])([F:30])[C:32]([F:35])([F:34])[F:33])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:20]([F:22])([F:21])[C:23]([F:25])([F:24])[C:26]([F:28])([F:27])[C:29]([F:31])([F:30])[C:32]([F:35])([F:34])[F:33]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: [Cu]
Solvent: CS(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1c2ccccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2ccccc12
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 9,10-dibromoanthracene (0.6 g, 1.78 mmol) and a copper powder (1.14 g, 17.8 mmol) were added to a 200 mL reaction vessel and were dissolved in anhydrous dimethyl sulfoxide (25 mL). α,α,α-Benzotrifluoride (25 mL) and C6F13I (1.96 mL, 8.93 mmol) were added thereto and reaction was carried out at 130° C. for 4 hours. After quenching with ice-water, the reaction solution was extracted with methylene chloride. Thereafter, the obtained organic layer was dried over anhydrous sodium sulfate and then filtrated. The filtrate was subjected to solvent removal on a rotary evaporator and, thereafter, separation and purification were conducted by using column chromatography. A 9,10-bis(perfluorohexyl)anthracene was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6][N:7]([C:15](=[O:40])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH3:1][O:2][C:3](=[O:41])[CH2:4][CH2:5][CH2:6][N:7]([C:15](=[O:40])[C:16]1[CH:17]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14]
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F
Reaction time: 16 h

Procedure:
A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino]-butyric acid methyl ester (0.020 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 16 h and then concentrated under reduced pressure to give the title compound (0.022 g) as a colourless gum.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]1(C)N([O])[C:13]([CH3:17])(C)[CH2:12][CH2:11][CH2:10]1.CC(N=NC(C#N)(C)C)(C#N)C>>[CH2:1]=[CH:2][C:3]1[CH:4]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:11]([O:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH2:12][CH2:13][CH3:17]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CC(=O)OCCCC
Product: C=Cc1ccccc1
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
Incorporation of maleic anhydride into an emulsion aggregation particle at the bulk polymerization step. A stock solution of styrene (390 ml) and butylacrylate (110 ml) was prepared and to 400 ml was added TEMPO (3.12 g 0.02 mole) and vazo 64 initiator (2.0 g, 0.0125 mole). This was heated under a nitrogen atmosphere to 135° C. (bath temperature) and then added to it dropwise a solution of maleic anhydride (9.8 g) in 100 mL, of the styrene/butylacrylate stock solution that had been deoxygenated using nitrogen. The addition was done over a 30 minute period after which it was stinted for 5 more minutes and then cooled to afford a poly(styrene/maleic anhydride-b-styrene/butylacrylate) (Mn=4,990 with PD=1.23) solution in styrene/butylacrylate monomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][C:25]([CH3:30])=[CH:26][C:27](Cl)=[O:28].O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:27](=[O:28])[CH:26]=[C:25]([CH3:30])[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1cccc(Nc2ccc(C)cc2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(N(C(=O)C=C(C)C)c2ccc(C)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 0.10 g (0.47 mmol) of N-(4-methylphenyl)-3-methoxyaniline (Compound 15) in 3.0 mL of tetrahydrofuran stirring at 0° C. under argon, were added 0.15 mL (0.11 g, 1.1 mmol) of triethylamine and then 0.19 g (1.6 mmol) of 3,3-dimethylacryloyl chloride. The reaction mixture was allowed to warm to room temperature over 30 minutes and then heated at 50° C. for 13 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with diethyl ether (2x). The combined organic layers were then washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give an oil. The mixture was purified by flash chromatography (10% ethyl acetate in hexanes, 20% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.75 (3 H, s), 2.16 (3 H, s), 2.34 (3 H, s), 3.76 (3 H, s), 5.61 (1 H, s), 6.75-6.81 (2 H, m), 7.08 (2 H, d, J=8.5 Hz), 7.14 (2 H, d, J=8.5 Hz), 7.23 (1 H, t, J=7.8 Hz).
Reaction SMILES: [N:1]1([C:7]([NH:9][NH2:10])=S)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:11][CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[ClH:11].[CH3:20][C:18]1[NH:10][N:9]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NNC(=S)N1CCOCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(N2CCOCC2)n[nH]c1C
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
A stirred slurry of 6.3 g (0.039 mole) of 4-morpholinecarbothioic acid hydrazide in 75 mL of absolute ethanol under nitrogen atmosphere was treated with 6.43 g (0.039 mole) of ethyl 2-chloroacetoacetate and the exothermic reaction mixture stirred at ambient temperature for 18 hr. The major portion of reaction mixture solids were dissolved by heating to reflux, the sulfur residue removed by filtration and the filtrate concentrated in vacuo to a solid, which was crystallized from 2-propyl alcohol to yield 5.5 g of white crystalline needles, mp 165°-173° C., as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (400 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (217 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, dimethyl sulfide (0.1 ml) was added. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) and recrystallized from diisopropyl ether→ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (245 mg) as yellow crystals (Compound 16).
Reaction SMILES: CN(C)C1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[O:10]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:4][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:9]1
Reactant: c1cn[nH]c1
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: c1cnn(CC2CCCOC2)c1

Procedure:
The title compound was prepared by substituting (tetrahydro-2H-pyran-3-yl)methanol for (3-(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.