Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(O)(=O)C>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
In a 1 liter round-bottom flask, triphenylmethanol (26.0 grams, 0.100 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) and aniline (14.6 milliliters, 0.160 mol) were added to a solution of concentrated aqueous hydrochloric acid (47 milliliters) in acetic acid (312 milliliters). The resulting solution was stirred and heated at reflux for 48 hours. The yellow solution was then cooled to room temperature and solvents were removed by evaporation under reduced pressure. Ethanol (700 milliliters) was added to dissolve all the off-white solid residue, and the stirred solution was cooled to −10° C. Sulfuric acid (52 milliliters) was then added, and the cold mixture was stirred for 20 minutes. Isopentylnitrite (31.2 milliliters; obtained from Aldrich Chemical Co.) was then added and the solution was stirred for an additional 20 minutes. Thereafter, hypophosphorous acid (89 milliliters, 50 percent by weight aqueous solution; obtained from Aldrich Chemical Co.) was added, still at −10° C., and the solution was gradually heated to reflux and stirred for 2 hours. The mixture was then cooled to room temperature, giving an off-white precipitate, which was recovered by filtration, successively washed with water, hexanes, methanol, ethanol, methanol, and finally with pentane, and dried under reduced pressure to give the targeted tetraphenylmethane as a colorless solid (28.0 grams, 90 percent yield).
Reaction SMILES: C1C2CCC3C=CC=CC=3N(C(Cl)=O)C=2C=CC=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1)[NH2:43].C1(C)C=CC=CC=1>C(O)C>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[Cl:39][C:40]1[CH:41]=[C:42]([NH:43][C:37]([NH:36][C:34]([N:24]2[C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[CH2:27][CH2:28][C:29]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]2=3)=[O:35])=[S:38])[CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N1c2ccccc2CCc2ccccc21
Agent: O=C(N=C=S)N1c2ccccc2CCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4c5ccccc5CCc5ccccc54)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was prepared using commercially available 10,11-dihydro-5H-dibenzo(b,f)azepin-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 50%).
Reaction SMILES: [C:1]([C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][N:7](C#N)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:25]>>[ClH:25].[C:1]([C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C#N)CC1
Agent: Cl
Product: CC(=O)C1(c2ccccc2Sc2ccccc2)CCNCC1

Procedure:
A solution of 4.8 g of 4-acetyl-1-cyano-4-(2-phenylthiophenyl)piperidine, Example 8, in 50 ml of 2 N hydrochloric acid is refluxed for 16 hours, effecting a white precipitate. The precipitate is collected by filtration and then washed twice with 50 ml portions of water and dried, providing 4-acetyl-4-(2-phenylthiophenyl)piperidine hydrochloride.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:61]=[CH:60][C:33]([CH2:34][C:35]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([CH3:48])[C:36]([NH:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[O:37])=[CH:32][CH:31]=2)=[N:28][CH:29]=1>C(Cl)Cl>[CH3:45][C:42]([CH3:46])([CH2:43][CH3:44])[CH2:41][C:40](=[O:47])[CH2:39][NH:38][C:36](=[O:37])[C:35]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([CH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:29][N:28]=2)=[CH:61][CH:60]=1)[CH3:48]
Reactant: CCC(C)(C)CC(O)CNC(=O)C(C)(Cc1ccc(-c2ccc(F)cn2)cc1)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C(C)(Cc1ccc(-c2ccc(F)cn2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (269 mg, 0.63 m mol) was added to an ambient temperature solution of benzyl {1-[4-(5-fluoropyridin-2-yl)benzyl]-2-[(2-hydroxy-4,4-dimethylhexyl)amino]-1-methyl-2-oxoethyl}carbamate (170 mg, 0.32 mmol) in methylene chloride (5 mL). After stirring at ambient temperature for 2 hr the reaction mixture was quenched with saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (1:1) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford benzyl {2-[(4,4-dimethyl-2-oxohexyl)amino]-1-[4-(5-fluoropyridin-2-yl)benzyl]-1-methyl-2-oxoethyl}carbamate which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:42][C:43]#[N:44]>C1COCC1>[C:43]([CH2:42][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=2)[N:19]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:44]
Reactant: N#CCBr
Reactant: COC(=O)[C@@H]1CC[C@H](c2cccc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2cccc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{3-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D43, 1.93 g, 4.7 mmol) in dry THF (20 mL) at −78° C. was added LiHMDS (5.2 mL of a 1M solution in THF, 5.2 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. Then the yellow slurry was cooled to −78° C. and bromoacetonitrile (2.2 mL, 30.9 mmol) was added. The reaction mixture was left under stirring for 1 h and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (1.15 g, 54%); 1H NMR (400 MHz, CDCl3) δ(ppm): 2/1 mixture of rotamers; 7.31-7.47 (m, 5H); 7.22-7.28 (m, 2H); 7.07-7.12 (m, 1H); 6.85-6.91 (m, 1H); 5.05-5.17 (m, 3H major+3H minor); 4.94 (bs, 1H major); 3.88 (br. s, 3H); 3.79 (br. s, 1H minor); 3.52 (d, 1H major); 3.05-2.28 (m, 1H major+1H minor); 2.62-2.77 (m, 1H); 2.39-2.57 (m, 1H); 2.23-2.33 (m, 1H); 1.92-2.08 (m, 1H); 1.44 (s, 9H minor); 1.14 (s, 9H major).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: ON=C1CCCCC1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(C)cc2)CC1
Product: Cc1ccc(N2CCN(CCCc3onc4c3CCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cyclohexanone oxime and ethyl 4-(4-(4-methylphenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazole is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=Cc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C=CC(=O)O)c1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
After a stirred mixture of 4.06 g (14 mmol) of methyl 3-[3-(tert-butoxycarbonyl aminomethyl)phenyl]-2-propenoate, 3.0 g (28.3 mmol) of sodium carbonate, 75 ml of water and 75 ml of methanol was heated at reflux for 5 hours, the produced methanol was distilled off and the solution was cooled to 0° C. and acidified with 1N hydrochloric acid. The resulting mixture was extrated with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. Recrystallization of the residual solid from 1:3 ethyl acetate-hexane gave 3.52 g (91%) of the product as crystals, mp 121°-123° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:2]=1>[Pd].C(O)C>[OH:22][CH:10]([CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: OC(CC#Cc1cccnc1)CCCCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Reaction time: 8 h

Procedure:
A mixture of 7.36 g (24 mmol) 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne, 100 mL ethanol and 0.74 g 10% palladium on charcoal is hydrogenated in a Parr apparatus at 3 atmospheres pressure and room temperature for 8 hours. The catalyst is filtered off and washed with ethanol. The combined filtrate is evaporated to give 5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3) delta 4.4 (brs,1H), 2.67 (t,2H).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C[Si](C)(C)[C:10]([F:13])([F:12])[F:11]>C1COCC1.F.C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:10]([F:13])([F:12])[CH:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCCCC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Solvent: C1CCOC1
Product: C=CCCCC(O)C(F)(F)F
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a ice-bath cooled solution of hex-5-enal (500 mg, 4.331 mmol) and trimethyl(trifluoromethyl)silane (0.74 g, 5.13 mmol, 1.2 equiv.) in THF (10 mL) was added tetrabutylammonium hydrofluoride (10 mg, 0.04 mmol). The ice bath was removed and the reaction progress was monitored via GCMS and 1H NMR. Upon complete transformation of the starting material the reaction mixture was treated with 2M HCl and stirred for an additional 2 h. Then, 50 mL of Et2O was introduced and the layers were separated. The aqueous fraction was additionally extracted with Et2O and the combined organic phases were washed sequentially with a saturated aqueous NaHCO3 solution, water, and brine. After drying with MgSO4 and filtration the solvent was removed under reduced pressure and the resultant crude residue was purified by column chromatography (silica gel, pentane/Et2O, v/v=8/2). Fractions containing the pure compound were collected and concentrated in vacuo to give 1,1,1-trifluorohept-6-en-2-ol (225 mg, 31% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.I[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][C:4]1[N:3]=[C:2]([NH:1][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:13][N:12]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Ic1nnc(Cc2ccncc2)c2ccccc12
Reactant: Cc1cc(N)nc(C)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nnc(Cc3ccncc3)c3ccccc23)nc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 308 mg (2.5 mMol) of 4-amino-2,6-dimethyl-pyrimidine and 694 mg (2.0 mMol) of 1-iodo-4-(4-pyridyl-methyl)-phthalazine in 20 ml of toluene, 415 mg (3.0 mMol) of K2CO3 and 231 mg (0.20 mMol) of tetrakis-(triphenylphosphin)-palladium are added, and the mixture is stirred during 1 h at RT and then 17 h at 110° C. The hot reaction mixture is filtrated, the remaining solid washed out with toluene and petrol ether and discarded. From the filtrate, product crystallizes after cooling. Filtration, washing with toluene/petrol other and recrystallization from boiling dioxane yields the title compound: m.p 232-233° C.; An. calc.(C20H18N6.0.10H2O): C, 69.79%; H, 5.33%; N, 24.42%; H2O, 0.52%; An. meas. C, 69.78%; H, 5.32%; N, 24.20%; H2O, 0.5%; FAB-MS (M+H)+=343.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(OCC)C>[CH2:12]([N:14]([CH2:15][CH3:16])[S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])=[O:9])[CH3:13]
Reactant: O=S(=O)(Cl)CCCCCCCl
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)S(=O)(=O)CCCCCCCl
Yield: 92.8 %

Procedure:
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a solution of diethyl ether (60 ml) and diethylamine (4.83g, 66 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation In vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-diethyl-6-chlorohexanesulfonamide (7.12 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]([O-])=O.[Na+]>S(=O)(=O)(O)O.O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cccc(NN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A stirred solution of 50.0 g (0.41 mole) of 3-methoxyaniline in 60 mL of concentrated sulfuric acid and 100 mL of water was cooled to -5° C., and a solution of 28.0 g (0.41 mole) of sodium nitrite in water was added slowly while maintaining the temperature of the reaction mixture below 0° C. The mixture was stirred at 0° C. for 1 hour, then added slowly to a chilled, stirred solution of 100 g (0.44 mole) of stannous chloride dihydrate in 300 mL of concentrated hydrochloric acid. After complete addition, the reaction mixture was allowed to warm to ambient temperature and stand for 16 hours. The reaction mixture was filtered and the filter cake made basic. The basic material was extracted with diethyl ether. The reaction mixture filtrate was also made basic and extracted with diethyl ether. The ether extracts were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to give 49.1 g of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].NC1C=C(Cl)C(O)=C(Cl)C=1.ClC1N=C(SC2C=C(C)C=C(C)C=2)C=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:72][CH2:73][N:74]1[CH2:78][CH2:77][CH2:76][CH2:75]1>O1CCCC1>[Cl:9][C:6]1[CH:5]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([S:17][C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:14]=[CH:13][N:12]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:72][CH2:73][N:74]1[CH2:78][CH2:77][CH2:76][CH2:75]1
Reactant: OCCN1CCCC1
Reactant: Cc1cc(C)cc(Sc2ccnc(Nc3cc(Cl)c(O)c(Cl)c3)n2)c1
Agent: Cc1cc(C)cc(Sc2ccnc(Cl)n2)c1
Agent: Nc1cc(Cl)c(O)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Sc2ccnc(Nc3cc(Cl)c(OCCN4CCCC4)c(Cl)c3)n2)c1

Procedure:
To a solution of N-(3,5-dichloro-4-hydroxyphenyl)-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine (1.0 g, 2.55 mmol—prepared from 4-amino-2,6-dichlorophenol and 2-chloro-4-(3,5-dimethylphenylsulphanyl)-pyrimidine according to the method of Example 4) in dry tetrahydrofuran were added triphenylphosphine (802 mg, 3.06 mmol) and N-(2-hydroxyethyl)pyrrolidine (0.3 ml, 2.55 mmol), followed by diethyl azadicarboxylate (0.49 ml, 3.1 mmol). The resulting solution was heated at reflux for 18 h and on cooling the reaction was partitioned between ethyl acetate (200 ml) and saturated aqueous NaHCO3 (200 ml). The organic phase was dried (MgSO4), evaporated and the residue columned (silica; ethyl acetate) to give the title compound (400 mg) as a white foam. δH 8.08 (1H, d, J 5.8 Hz), 7.56 92H, s), 7.17 (2H, s), 7.09 (1H, s), 7.05 (1H, s), 6.28 (1H, d, J 5.8 Hz), 4.18 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6 Hz), 2.69 (4H, m), 2.31 (6H, s) and 1.80 (4H, m). MS m/z 489.2/490.9 (MH+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][CH:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:20][OH:21]>O1CCOCC1>[F:24][C:23]([F:26])([F:25])[CH2:22][CH:19]([NH:18][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:20][OH:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CO)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NC(CO)CC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 0.38 ml of 50% strength aqueous potassium carbonate solution (1.7 mmol, 0.68 equivalents) and 0.54 ml of benzyl chloroformate (3.8 mmol, 1.5 equivalents) were added to 400 mg of rac-2-amino-4,4,4-trifluorobutan-1-ol (Example 144A, 2.5 mmol, purity about 90%, 1 equivalent) in 36 ml of 1,4-dioxane, and the mixture was stirred at RT for 2 h. Another 0.11 ml of benzyl chloroformate (0.76 mmol, 0.3 equivalents) and 0.08 ml of 50% strength aqueous potassium carbonate solution (0.35 mmol, 0.14 equivalents) were then added, and the mixture was stirred at RT for a further 30 min. After concentration under reduced pressure, the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The crude product obtained was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 490 mg (70% of theory) of the title compound.
Reaction SMILES: [OH-:1].[Na+].[I:3][C:4]1[C:11]([I:12])=[CH:10][C:9]([I:13])=[CH:8][C:5]=1[CH2:6]Br.O>CN1C(=O)CCC1>[I:3][C:4]1[C:11]([I:12])=[CH:10][C:9]([I:13])=[CH:8][C:5]=1[CH2:6][O:1][CH2:6][C:5]1[CH:8]=[C:9]([I:13])[CH:10]=[C:11]([I:12])[C:4]=1[I:3]
Reactant: [OH-]
Reactant: BrCc1cc(I)cc(I)c1I
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Ic1cc(I)c(I)c(COCc2cc(I)cc(I)c2I)c1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
447 mg of PVA 13 kDa (9 mmol, 1 eq) was dissolved in 30 ml of dry NMP (concentration of PVA: 0.3M) under nitrogen gas flow. The reaction mixture was stirred for 5 minutes at 130° C.; then the temperature was decreased to 50° C. 727 mg of ground and dried NaOH (18 mmol, 2 eq) was added and the mixture was stirred for 10 minutes. Then, 5 g of 2,3,5-triiodobenzyl bromide (9 mmol, 1 eq) was added. After 30 minutes, the mixture was cooled to room temperature and 30 ml of cold water was added under stirring. A solid precipitate appeared, was filtered and washed with methanol. After conventional steps of purification, 800 mg of TIB-PVA 13 kDa including 26% of residual NMP was obtained (representing 208 mg of NMP and 592 mg of TIB-PVA 13 kDa).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])=[S:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Solvent: Cc1ccccc1
Product: Fc1cc(C(F)(F)F)ccc1C(=S)Nc1ccc(Br)cc1
Temperature: 25 °C
Yield: 162.2 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (3.97 g, 0.0098 mol) was heated in toluene at reflux under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:8) as mobile phase to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzenecarbothioamide (6.0 g, 0.0159 mol) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4].S(Cl)([Cl:23])(=O)=O.N>ClCCl>[CH3:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([Cl:23])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(=O)Nc1sccc1C(=O)c1ccccc1F
Agent: N
Solvent: ClCCl
Product: CCC(=O)Nc1sc(Cl)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.50 g of 2-(N-methylacetylamino)-3-(o-fluorobenzoyl)thiophene in 50 ml of dichloromethane is added dropwise 2.16 g of sulfuryl chloride in 30 ml of dichloromethane. After stirring the reaction mixture for overnight at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to a residue. The residue is chromatographed on silica gel using chloroform as an eluent to give 2-(N-methylacetylamino)-3-(o-fluorobenzoyl)-5-chlorothiophene as an oil.