Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Reactant: NC1CCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(Br)cc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in DMF (9 mL) were added cyclobutanamine (81.5 mg, 1.15 mmol), DIPEA (370 mg, 2.86 mmol). The reaction mixture was stirred in autoclave at 90° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 28%). NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.42 (m, 2H), 3.96 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.74 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][S:16](=[O:23])(=[O:22])[C:15]=3[C:24]=2[CH3:25])=[O:10])[CH:5]=[N:4]1)[CH3:2].[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]([O:8][C:26]([CH2:27][CH2:28][CH3:29])=[O:30])=[C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][S:16](=[O:23])(=[O:22])[C:15]=3[C:24]=2[CH3:25])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)S(=O)(=O)CCS3(=O)=O)c1O
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Oc1c(C(=O)c2ccc3c(c2C)S(=O)(=O)CCS3(=O)=O)cnn1CC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
1.5 g (3.9 mmol) of 1-ethyl-5-hydroxy-4-(8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz[1,4]dithiin-7-yl)carbonylpyrazole were suspended in 20 ml of methylene chloride, and 0.42 g (3.9 mmol) of butyryl chloride and 0.39 g (0.42 mol) of triethylamine were added. After five hours of stirring at 20° C., the mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and water, dried and filtered off, and the solvent was distilled off. The residue was subsequently chromatographed over silica gel (mobile phase: ethyl acetate/cyclohexane=2/3).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][C@@H:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][CH2:16][CH2:15][C@@H:6]1[CH2:5][C:4]2[C:3]3[C:2]([Cl:1])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 2-[(12S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2 (7),3,5-tetraen-12-yl]ethan-1-ol (300 mg, 1.12 mmol, 1.00 equiv) in 5 mL of distilled DMF was added TBSCl (252 mg, 1.50 equiv) and imidazole (137 mg, 2.01 mmol, 1.80 equiv) at room temperature under nitrogen. The resulting solution was stirred for 1 h at ambient temperature, quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to provide (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (420 mg, 98%) as a light yellow solid. MS (ES): m/z 384, 386 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH:14]([CH3:16])[CH3:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C#N)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a stirred solution of 50% sodium hydroxide (5.2 g, 65.2 mmol) there was added 4-fluorophenylacetonitrile (10.0 g, 74.1 mmol), sodium hydroxide pellets (0.7 g, 18.5 mmol) and tetrabutylammonium chloride (3.3 g, 14.1 mmol) and the reaction mixture was heated to 45° C. To the reaction mixture there was added 2-bromopropane (10.0 g, 81.5 mmol) and the reaction mixture heated at 60°-65° C. for 1 hour, and then at 90°-95° C. for 1 hour. The reaction mixture was cooled to ambient temperature. The reaction mixture was diluted with a mixture of 1:1 diethyl ether/water (100 mL). The layers were separated and the aqueous layer was washed with diethyl ether (25 mL). The organic layers were combined, washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30/70 methylene chloride/hexane) to give 9.4 g (71% yield) of 4-fluoro-a-(1-methylethyl)benzeneacetonitrile as a white oil. 1H NMR (300 MHz, CDCl3) d 7.31 (m, 2H), 7.08 (m, 2H), 3.65 (d, 1H), 2.12 (m, 1H), 1.07 (d, 3H), 1.03 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH2:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of commercially available methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (100 mL) was added 2-phenoxyacetyl chloride (6.60 mL, 47.8 mmol). The white suspension formed was cooled to 0° C. and treated with triethylamine (13.3 mL, 95.6 mmol) dropwise. The resulting solution was stirred at room temperature for 0.5 hours. The mixture was diluted with CH2Cl2 and was washed with water and saturated aqueous NH4Cl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 7% EtOAc-Heptane), affording the title compound.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>O.O1CCCC1>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (67.7 g) in a mixture of water (920 ml) and tetrahydrofuran (300 ml) was added aqueous sodium hydroxide solution (46-48% w/w; 24 ml) followed by water (40 ml). The resulting hazy, pale yellow solution was cooled to 20° C. before adding 2,3-difluorobenzyl bromide (83.0 g) uniformly over 25 minutes, to yield a white precipitate. The mixture was stirred at ambient temperature for 3.5 hours, the product collected and washed twice with a mixture of water (68 ml) and tetrahydrofuran (24 ml), to afford the title compound as a white solid (101.89 g).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:6].[CH3:14][C@@H:15]([CH2:31][CH3:32])[CH2:16][CH2:17][CH2:18]OC1C=C(S([O-])(=O)=O)C(C)=CC=1.CC(CC)CCCO>CO>[CH3:14][C@@H:15]([CH2:31][CH3:32])[CH2:16][CH2:17][CH2:18][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC[C@H](C)CCCOc1ccc(C)c(S(=O)(=O)[O-])c1
Agent: CCC(C)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)CCCOc1ccc(C(=O)OC)cc1
Yield: 97 %

Procedure:
KOH (5 g, 0.09 mol) was added to a solution of methyl p-hydroxybenzoate (13.6 g, 0.09 mol) dissolved in methanol (66 ml), followed by dissolving these together on heating, adding (S)-p-(4-methylhexyloxy)toluenesulfonate (20 g, 0.07 mol) prepared from 4-methylhexanol in the same manner as in Example 1, (ii), heating the mixture under reflux for 10 hours, extracting the reaction mixture with toluene after completion of the reaction, distilling off the solvent, to obtain methyl (S)-p-(4-methylhexyloxy)benzoate (17 g), adding to a solution of this product dissolved in ethanol (7.5 ml), a solution of NaOH (4.9 g, 0.14 mol) dissolved in water (24.6 ml), heating the mixture under reflux for 5 hours, pouring the resulting reaction mixture into 6N-hydrochloric acid (90 ml) having the ice added, allowing the mixture to stand overnight, recrystallizing the resulting crystals from heptane to obtain (S)-p-(4-methylhexyloxy)benzoic acid (6.5 g), adding thionyl chloride (20 ml) to the benzoic acid (5 g, 0.02 mol), heating the mixture under reflux for one hour, and distilling off excess thionyl chloride to obtain p-(4-methylhexyloxy)benzoic acid chloride (XI) (5 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.I[CH3:14].[NH4+].[Cl-]>C1COCC1>[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][CH3:14])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(F)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCc1ccc(F)cc1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 145 mg, 3.62 mmol) was slowly added to a solution of 4-fluorophenethyl alcohol (338 mg, 2.41 mmol) in THF (5 mL) at room temperature and with stirring. At the end of the addition, the solution had become cloudy. The reaction mixture was heated to 60° C. for 2 h and then cooled to 0° C. Iodomethane (225 μL, 3.62 mmol) was slowly added to the solution and the reaction mixture was stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0° C., neutralized with aq. sat. NH4Cl (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3×20 mL), brine (20 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc/hexanes=1/3) gave 169 mg (1.09 mmol) of the title product. Yield: 45%, pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.18 (dd, J=8.5, 5.6, Hz, 2H), 6.98 (apparent t, J=8.7 Hz, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 2.86 (t, J=6.9 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ 161.7 (d, J=242.2 Hz), 134.8 (d, J=3.2 Hz), 130.4 (d, J=7.7 Hz), 115.3 (d, J=20.9 Hz), 73.7, 58.8, 35.5 ppm. 19F NMR (282 MHz, CDCl3): δ −113.3 (m) ppm.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:40][CH3:41])=[C:7]([CH:29]=[C:30]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH:31]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[C:21]([N:23]1CCO[CH2:25][CH2:24]1)=[O:22])([CH3:4])([CH3:3])[CH3:2].N1C=CN=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1>[C:1]([C:5]1[C:6]([O:40][CH3:41])=[C:7]([CH:29]=[C:30]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH:31]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[C:21]1[O:22][CH:25]=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)N2CCOCC2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]nn1
Solvent: O=S1(=O)CCCC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2-c2ncco2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 130 °C
Yield: 46 %

Procedure:
To a solution of the product from Example 27, Part A (80 mg, 0.15 mmol) in tetramethylene sulfone (1.5 ml) was added 1H-1,2,3-triazole (10 μL, 0.17 mmol) and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated for 35 min at 130° C. in a microwave reactor. After cooling to room temperature, the mixture was partitioned between 1 N aqueous HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (37 mg, 46%). 1H NMR (300 MHz, DMSO-d6) 311.41 (d, J=1.84 Hz, 1 H) 10.10 (s, 1 H) 8.29 (d, J=1.10 Hz, 1 H) 8.05 (d, J=16.18 Hz, 1 H) 7.95 (d, J=8.82 Hz, 1 H) 7.82 (d, J=2.21 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 7.51 (d, J=2.57 Hz, 1 H) 7.46 (d, J=0.74 Hz, 1 H) 7.39 (dd, J=8.64, 2.39 Hz, 1 H) 7.20-7.30 (m, 2 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 3.80 (s, 3 H) 3.07 (s, 3 H) 1.38 (s, 9 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]1([CH3:75])[CH:57]=[CH:56][C:55]([S:58]([O:61][CH2:62][CH2:63]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:14]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:24]1)=[O:22])[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:63][CH2:62][O:61][S:58]([C:55]3[CH:56]=[CH:57][C:52]([CH3:75])=[CH:53][CH:54]=3)(=[O:60])=[O:59])=[CH:7][CH:6]=2)[CH:9]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
82.0 mg (0.13 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 7a) were dissolved in 5.1 ml N,N-dimethylformamide. 129 mg (0.40 mmol) cesium carbonate and 73.2 mg (0.20 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 20 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 64 mg (59%) tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:2]=1.N([O-])=O.[Na+].[I-:18].[K+]>Cl.O>[CH:2]1[C:3]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:5]=[C:6]([I:18])[CH:1]=1
Reactant: [I-]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 73.5 %

Procedure:
To a solution of 4-(pentafluorothio)aniline (15.0 g, 68.4 mmol) and ice (40.0 g) in hydrochloric acid (12M, 30 ml) was added a solution of sodium nitrite (5.0 g, 72.5 mmol) in water (120 ml) at 0° C. After stirring for 2 min, the mixture was added to potassium iodide (13.0 g, 78.3 mmol) in water (120 ml), ensuring the temperature did not rise above 10° C. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 60 h. The mixture was extracted with diethyl ether (2×100 ml) and the combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 300 g), eluting with diethyl ether:cyclohexane [1:10]. The appropriate fractions were combined and concentrated to give the title compound (16.6 g).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:4]([C:22](O)=[O:23])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C.Cl>O1CCCC1.C(OCC)C.O>[CH:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:6][CH:1]=1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
A solution of 0.5 g of the methyl ester of phenolphthalin prepared instep (ii) dissolved in 30 ml dry tetrahydrofuran was slowly added to a suspension of 0.5 g of lithium aluminum hydride in 20 ml dry tetrahydrofuran. The resulting reaction mixture was heated at reflux for 30 minutes, and then excess ethylacetate was added. The reaction mixture was poured into 1 N HCl, extracted with two 200 ml portions of ethyl etherand the ether evaporated leaving a residue of solid and some water. The residue was taken up in ethyl ether and the ether decanted from water, dried over sodium sulfate, filtered and the solvent removed in vacuo to give 0.42 g of phenolphthalol as a white solid. TLC on silica gel using ether showed the title compound as one major spot, and nmr was consistent with the phthalol structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>ClC(Cl)C>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 130 mmol) in anhydrous dichloroethane (450 mL), cooled in an ice bath, was added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous dichloroethane) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) was added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction was cooled in an ice bath. Water (300 mL) was added, maintaining the temperature of the reaction below 25° C., and the reaction was stirred at room temperature for 18 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:31][CH2:30][CH2:28][OH:29])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Product: OCCNc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 73 %

Procedure:
A mixture of 130 mg of 6-chloro-N-(4-phenoxyphenyl)pyridin-2-amine in 214 mg of ethanolamine was filled in a screw cap vial and was treated analogously to the method as set out in Example 16b, but using for flash column chromatography a solvent mixture of EtOAc:PE=1:1 instead of EtOAc:PE=3:1). 2-(6-(4-Phenoxyphenylamino)pyridin-2-ylamino)ethan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[C:22]#[N:23].[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:22]#[N:23]
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2C#N)SCC(=O)N1
Agent: [S]
Product: CC1=C(c2ccncc2C#N)SCC(=O)N1
Yield: 10.6 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-cyano-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (0.5 g) and sulfur sublimed (2.5 g) was treated in the same manner as described in Example 4 (ii) to give the titled compound (0.03 g, yield 10.6%) as pale orange powder. Chloroform-methanol (=20:1) was used as a developing eluant.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11](OC(=O)C)(=O)C>O>[CH2:11]=[C:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10]
Reactant: O=C1CCCc2sccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: C=C1CCc2sccc2C1=O
Temperature: 122 °C
Reaction time: 1 h

Procedure:
To 20.0 mL of tetramethyldiaminomethane was added 10.0 g of 6,7-dihydrobenzo[b]thiophen-4(5H)-one all at once. To this mixture was added 20.0 mL of acetic anhydride, dropwise. The reaction mixture exothermed to 45° C. and was heated to 122° C. for 15 minutes and then cooled to 90° C. where it was kept for 60 minutes. The dark solution was poured into cold water and extracted with ether. The ether was extracted with a saturated solution of NaHCO3 and then washed with brine. The ether layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The yellow oil was flash-chromatographed using 10% ethyl acetate and 90% hexanes as eluent to afford 6.18 g of a white solid, m.p. 47°-49° C. 200 MHz1H NMR(CDCl3) δ2.97 (t, 2H), 3.07 (t, 2H), 5.46 (s, 1H), 6.17 (s,1H), 7.11 (d, 1H), 7.48 (d, 1H); I. R. (Nugol) 1660 cm-1.