Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=1C.[CH2:40]([N:44]([C:88]1[CH:93]=[CH:92][C:91]([CH2:94][C:95]([O:97]CC)=[O:96])=[CH:90][CH:89]=1)[C:45]([C:47]1[C:51]([Cl:52])=[C:50]([CH3:53])[N:49]([C:54]2[CH:59]=[CH:58][C:57]([C:60](=[O:75])[NH:61][S:62]([C:65]3[CH:74]=[CH:73][C:72]4[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=4)[CH:66]=3)(=[O:64])=[O:63])=[CH:56][C:55]=2[C:76]([N:78]2[CH2:87][CH2:86][C:85]3[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=3)[CH2:79]2)=[O:77])[N:48]=1)=[O:46])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([C:88]1[CH:89]=[CH:90][C:91]([CH2:94][C:95]([OH:97])=[O:96])=[CH:92][CH:93]=1)[C:45]([C:47]1[C:51]([Cl:52])=[C:50]([CH3:53])[N:49]([C:54]2[CH:59]=[CH:58][C:57]([C:60](=[O:75])[NH:61][S:62]([C:65]3[CH:74]=[CH:73][C:72]4[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=4)[CH:66]=3)(=[O:63])=[O:64])=[CH:56][C:55]=2[C:76]([N:78]2[CH2:87][CH2:86][C:85]3[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=3)[CH2:79]2)=[O:77])[N:48]=1)=[O:46])[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(CC(=O)OCC)cc1
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(CC(=O)O)cc1
Yield: 6.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1F, ethyl 2-(4-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)phenyl)acetate (Example 155, 1 mg, 9.9 μmol) was converted to the title compound (0.5 mg, 53%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.71 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 8.06 (s, 2H), 8.03-7.97 (m, 2.5H), 7.94-7.91 (m, 0.5H), 7.73-7.65 (m, 2H), 7.41 (br s, 0.5H), 7.30 (br s, 0.5H), 7.23-7.10 (m, 5H), 7.03-6.96 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.61 (br s, 1H), 4.73 (br s, 1H), 4.48-4.19 (m, 2H), 4.07 (br s, 1H), 3.91 (br s, 1H), 3.54-3.39 (m, 2H), 2.95-2.75 (m, 2H), 2.10 (s, 2H), 2.01 (s, 1H), 1.65-1.55 (m, 1H), 1.40-1.18 (m, 5H), 0.92-0.80 (m, 3H); MS(ESI+) m/z 818.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) in N,N-dimethylformamide (100 ml) were added N-(3-bromopropyl)phthalimide (9.27 g, 35 mmol) and potassium carbonate (4.93 g, 36 mmol), followed by stirring at 60° C. for 6 hours. After allowing to stand overnight, the reaction solution was poured into water, and the insoluble matter was collected by filtration and washed with ethyl acetate and dried under reduced pressure to give N-[3-(4-chloro-3-nitrophenoxy)-propyl]phthalimide (7.78 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[C:16]([N+:31]([O-])=O)[CH:15]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:31][C:16]3[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][C:17]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: CCCOc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCCOc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 55a (273 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (187 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.62-1.79 (m, 2H) 2.34 (s, 3H) 2.76 (s, 3H) 3.86 (t, J=6.43 Hz, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.84 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.24 (d, J=8.46 Hz, 2H) 7.29 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.42 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 11.01 (s, 1H) 14.39 (s, 1H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
0.71 ml (0.71 mmol, 2.98 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 122.8 mg (0.238 mmol) 3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (55) in 5 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 90 min at 0° C. and then for 5 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 119.3 mg (0.24 mmol, 99.91%) 3-(3′-Benzyl-4″-hydroxy-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (56) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.86 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.87 (m, 1H, CH), 2.43 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.09 Hz, CH2), 2.61 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.93 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.95 (s, 2H, CH2Ph), 5.51 (s, 1H, OH), 6.88 (d, 1H, J=2.05 Hz), 6.95 (m, 2H), 6.97-7.26 (m, 11H). MS (EI): m/z=502 (40), 501 (100), 458 (4), 367 (10), 327 (7), 307 (8), 263 (8), 91 (43). HR-MS (EI): Calcd. for C36H39NO: 501.303164. Found: 501.303902.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[C:10]([C:7]1[S:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1nc(CN=[N+]=[N-])cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc(CN)cs1
Temperature: 60 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (1.08 g, 6.13 mmol) in dry DMF (21 mL) and treated with NaN3 (1.20 g, 18.39 mmol) at 65° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(4-(azidomethyl)-thiazol-2-yl)-ethanone as a yellow oil. To a solution of the crude azide (200 mg, 1.10 mmol) in THF (6 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The org. layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH-Et3N). LC-MS-conditions 01: tR=0.26 min; [M+H]+=157.04.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Product: CC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH:25]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[NH:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC.O.O1CCCC1>[C:53]([O:52][C:50](=[O:51])[N:42]([CH2:32][C:29]1[CH:28]=[N:27][C:26]([CH:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:23])=[O:24])[C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])=[CH:31][CH:30]=1)[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc(CO)cn1)c1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
Under a nitrogen atmosphere, diisopropyl azodicarboxylate (128 μl, 0.653 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine (178 mg, 0.435 mmol) obtained in Example 43, di-t-butyl iminodicarboxylate (142 mg, 0.653 mmol) and triphenylphosphine (171 mg, 0.653 mmol). The resulting mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and brine. The resulting organic layer was dried over sodium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (78 mg, 0.128 mmol, 32%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:10][N:11]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[C:3]=12
Reactant: Fc1cnc2cn[nH]c2c1Cl
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1cc2ncc(F)c(Cl)c2n1
Product: CC(C)(O)Cn1ncc2ncc(F)c(Cl)c21
Temperature: 110 °C

Procedure:
To a solution of 7-chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridine (300 mg, 1.749 mmol) in DMF (5 mL) was added Cs2CO3 (855 mg, 2.62 mmol) and 1-chloro-2-methylpropan-2-ol (209 mg, 1.924 mmol) and the mixture was heated at 110° C. for 2 hours. Water (20 mL) was then added and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give 1-(7-chloro-6-fluoro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol and 1-(7-chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-methylpropan-2-ol which were used i without further purification. MS [M+H] found 244.2.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:16][C:17]#[N:18]>C1COCC1.CCCCCC.CCOCC>[C:17]([CH2:16][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)#[N:18]
Reactant: C1=Cc2ccccc2C1
Reactant: N#CCCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC1=CCc2ccccc21
Temperature: 25 °C

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:28])=[O:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The alcohol from Example 1 (33.1 g) and 20 ml of triethylamine were dissolved in 350 ml of dichloromethane, cooled to 0° C., and treated with 11 ml methanesulfonyl chloride. After being stirred at room temperature for about 20 hours, the reaction mixture was diluted with dichloromethane (100 ml) and the organic layer was washed with three 50-ml portions of water and one of brine. Drying and concentration in vacuo gave the crude product which gradually crystallized upon standing. The solid was washed with diethyl ether, filtered, and dried to yield 12.0 g of 2-[2-(methylsulfonyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a white powder; m.p. 106°-108° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([Cl:24])=[N:7][C:8]2[N:9]([N:21]=[CH:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:32]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)Cl>[Si:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([Cl:24])=[N:7][C:8]2[N:9]([N:21]=[CH:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH3:20])=[CH:16][CH:17]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(Nc2c(CCCO)c(Cl)nc3ccnn23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Nc2c(CCCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.9 %

Procedure:
To a methylene chloride (14 mL) solution containing [6-(3-hydroxypropyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)amine (1.43 g, 4.12 mmol), triethylamine (861 μL, 6.18 mmol) and tert-butylchlorodimethylsilane (808 mg, 5.36 mmol) were added with ice-cooling, and this mixture was stirred at room temperature for 16 hr. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (10 to 15% ethyl acetate-hexane) to obtain the title compound (2.03 g, yield 100%).
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.N1(CCCCNC2N=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N:32]=2)CCOCC1.C(O)(C(F)(F)F)=[O:42].N>C(Cl)Cl>[N+:29]([C:30]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][CH2:37]2)=[CH:33][C:31]=1[NH:32][C:10](=[O:11])[CH3:12])([O-:40])=[O:42]
Reactant: [O-][n+]1nc(NCCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 3.6 mL, ca. 72 mmol) was added dropwise to a stirred solution of TFAA (10.2 mL, 72 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 62 (2.48 g, 7.2 mmol) and TFA (2.8 mL, 36 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 20° C. for 16 h, cooled to 0° C. and made basic with dilute aqueous NH3 solution and stirred vigorously for 30 min. The mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 62 (981 mg, 40%) and (ii) 1,4-dioxide 63 (504 mg, 19%) as a red solid: mp (MeOH) 140-141° C.; 1H NMR δ 8.09 (s, 2H, H-5, H-9), 7.32 (br s, 1H, NH), 3.74 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.57-3.63 (m, 2H, CH2N), 3.09 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.50-2.55 (m, 4H, 2×CH2N), 2.47 (br t, J=7.1 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.71-1.79 (m, 2H, CH2), 1.61-1.69 (m, 2H, CH2); 13C NMR δ 155.9, 149.5, 145.8, 137.9, 129.8, 115.7, 111.6, 66.6 (2), 58.1, 53.5 (2), 41.2, 33.4, 32.4, 27.1, 25.5, 23.4; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15]Cl>ClC1C=CC(C)=CC=1>[Cl:15][C:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Reactant: ClCl
Solvent: Cc1ccc(Cl)cc1
Product: Clc1cccc2c1Sc1ccccc1S2
Reaction time: 4 h

Procedure:
Twenty parts of thianthrene dissolved in 142 parts of monochlorotoluene (a commercial mixture of about 50 percent ortho- and 50 percent para-chlorotoluene) were charged to a batch type stirred tank reactor together with 0.2 part of SbCl3. Chlorine was fed to the reaction mixture at about 0.35 parts/min. for a 4 hour period. The mixture was then cooled and 14.5 parts of chlorothianthrene were obtained which had 68.03 percent 2,3,7,8 -tetrachlorothianthrene. Part of this sample was recrystallized from tetrahydrofuran to produce 95.3 percent 2,3,7,8-tetrachlorothianthrene, melting point 250°-255° C. Another 3.7 parts were recovered as a second crop from the mother liquor, giving a total yield of 19.2 parts of chlorothianthrene. This second crop was low melting with 43.25 percent of the 2,3,7,8 -isomer indicating that the composition was a mixture of 2-chloro-, 2,7-dichloro-, and other isomers with 2,3,7,8-tetrachlorothianthrene.
Reaction SMILES: [I-:1].[OH:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([OH:13])=[C:5]([CH3:14])[C:4]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O=O>C(Cl)Cl>[I-:1].[CH3:12][O:11][C:7]1[C:6](=[O:13])[C:5]([CH3:14])=[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3](=[O:2])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(O)c(C)c(CCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Agent: O=O
Agent: [I-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 13 (2.07 g) in CH2Cl2 (50 mL) was saturated with oxygen gas and a solution of NO2 in CH2Cl2 (0.5 mL, 1.32 M) was added. The reaction was then stirred at room temperature under an oxygen atmosphere for 18 hrs. The solvent was removed in vacuo to afford the crude product [5-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)pentyl]triphenylphosphonium iodide (14) as a red oil. This residue was re-dissolved in CH2Cl2 (10 mL) and triturated in ether (200 mL) to give an initial yellow precipitate which congealed into a red oil in a few minutes. The solvents were decanted and the precipitate dissolved in CH2Cl2 and the solvent removed in vacuo to give the product (14) (1.866 g) as a red oil. An aliquot (0.880 g) of 14 was purified by column chromatography on silica gel (20 g). Elution with CH2Cl2 gave some unidentified purple coloured material. Elution with 5% ethanol/CH2Cl2 gave the pure iodide product 14 (0.606 g) as a red oil. 1H NMR δ 7.84-7.68 (15H, m, Ar—H) 3.98 (6H, s, 2×Ar—OMe), 3.65 (2H, m, CH2—P+), 2.40 (2H, t, J=7.5 Hz, Ar—CH2), 2.00 (3H, s, Ar-Me), 1.71 (4H, m, —CH2—), 1.43 (2H, m, —CH2—) ppm. 31P NMR (121.4 MHz) δ 25.47 ppm. Anal. calcd. for C32H36IO4P: C, 59.8; H, 5.7; I, 19.8; P, 4.8. Found: C, 60.0; H, 5.3; I, 19.7; P, 4.7%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH2:19](O)[CH3:20].[K+].[Br-]>C(O)(=O)C>[CH2:19]([O:13][C:12]1[NH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1)[CH3:20]
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: CCO
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1nnc(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 24 °C

Procedure:
5-[4-(Trifluoromethyl)phenyl]1,3,4-oxadiazol-2-amine (10 g, 44 mmol) and potassium hydroxide (7.4 g, 0.132 mol) dissoved in abs. ethanol (300 ml) were heated at reflux for 3 h. After being cooled to 24° C., the solution was neutralized with acetic acid and concentrated by rotary evaporation. The residue was taken up in ethyl acetate and washed with water and brine. Recrystallization from acetonitrile/ether (2:1) gave 9 g (82%); mp 151-152° C.; IR(KBr, υ=cm-1) 2996, 1534, 1460, 1330, 1162, 1130, 1070; 1H NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t, J=7.1 Hz), 4.38 (2H, q, J=7.0 Hz), 7.82 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.1 Hz), 13.64 (1H, br. s); MS(DCl)m/z: 258 (MH+)