Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 1-methyl-1,4-diazepane (1 g, 8.8 mmol) in DMSO (20 mL) were added K2CO3 (2.4 g, 18 mmol) and 5-bromo-2-nitropyridine (51-7) (1.78 g, 8.8 mmol). The mixture was stirred at 65° C. for overnight. It was allowed to cool to room temperature and poured into water. The resulting solid was collected and dried under vacuum. The solid was further purified by flash column eluting with 3:1 petroleum ether/ethyl acetate and then methylene chloride to give 338a as a yellow solid (800 mg, 69%). MS: [M+H]+ 236.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([N:11]([C:13]2[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:31]([OH:46])[C:32]([N:34]3[CH2:45][CH2:44][CH2:43][C@H:35]3[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=2)[CH3:12])=O)=CC=1)([O-])=O.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>>[O:61]1[CH2:62][CH2:63][N:58]([C:9]([N:11]([C:13]2[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:31]([OH:46])[C:32]([N:34]3[CH2:45][CH2:44][CH2:43][C@H:35]3[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=2)[CH3:12])=[O:8])[CH2:59][CH2:60]1
Reactant: C1COCCN1
Reactant: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Product: CN(C(=O)N1CCOCC1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 144 h

Procedure:
A solution of 47 mg (0.060 mmol) of 1-[(2S,3S)-3-{N2 -[4-(P-N-nitrophenoxycarbonyl-N-methylamino)-phenoxy]acetyl-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 42) dissolved in 0.5 ml of morpholine was allowed to stand at room temperature for 6 days. At the end of this time, the reaction mixture was freed from an excess of morpholine by distillation under reduced pressure, and the residue was diluted with chloroform and then washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative thin layer chromatography, using a 8:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 30 mg of the title compound as a colorless powder, melting at 112°-114° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[O:8]1)[O:9][CH2:10]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CNC(=O)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane was added of pivaloyl chloride (60 μL, 0.05 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6.8 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.37 (s, 1H), 7.16 (s, 1H), 7.10 (s, 4H), 5.07 (s, 2H), 4.12 (d, J=15.8 Hz, 1H), 4.04 (d, J=15.8 Hz, 1H), 3.82-3.59 (m, 3H), 3.45-3.39 (m, 2H), 3.43 (dd, J=9.9, 8.4 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.11 (s, 9H); MS ESI (m/z) 504 (M+1)+, calc. 503.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C)=[N:7][CH:8]=1.O[C:11]1C(C)=NC=CC=1.CI>>[CH3:1][O:2][C:3]1[C:8]([CH3:11])=[N:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ncccc1O
Reactant: COc1ccc(C)nc1
Solvent: CI
Product: COc1cccnc1C

Procedure:
Was prepared in a similar manner to 5-methoxy-2-methylpyridine using 3-hydroxy-2-methylpyridine (purchased from Fisher Scientific) and methyl iodide (purchased from Fisher Scientific).
Reaction SMILES: FC(F)(F)S([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)=O.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>CN(C=O)C.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][Si:31]([C:34]#[C:35][C:6]1[C:14]2[S:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: CCNC(=O)Nc1nc2cccc(S(=O)(=O)C(F)(F)F)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)Nc1nc2cccc(C#C[Si](C)(C)C)c2s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
A mixture of 1-(7-trifluoromethylsulfonyl-2-benzothiazolyl)-3-ethylurea (0.080 g, 80% pure, 0.17 mmol), Pd(PPh3)2Cl2 (0.010 g, 0.014 mmol, 0.08 eq), and triethylamine (0.102 mL, 0.73 mmol, 4.3 eq) in 1 mL of anhydrous DMF was bubbled with nitrogen gas for 5 minutes, followed by the addition of trimethylsilyl acetylene (0.12 mL, 0.85 mmol, 5.0 eq). The mixture was heated at about 100° C. with stirring in a sealed tube for about 18 hours. The mixture was cooled down, taken up in 10 mL MeOH, and evaporated to dryness. Purification by flash chromatography on SiO2 with ethyl acetate and heptane (2/1) gave pure desired compound 0.050 g (93%). LC/MS 318 (M+1); LC retention time 9.25 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:6][C@@H:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:39]I>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:6][C@@H:7]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([N:22]([CH3:39])[C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: COc1ccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC
Reactant: CI
Product: COc1ccc(O[C@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 531.2 (M+H)+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][N:47]([CH3:95])[CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:64]=[C:65]4[C:71]([C:72]5[CH:73]=[N:74][N:75]([CH2:77][C:78]6[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=6)[CH:76]=5)=[CH:70][N:69](S(C5C=CC(C)=CC=5)(=O)=O)[C:66]4=[N:67][CH:68]=3)=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)=[O:50].[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][N:47]([CH3:95])[CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:58]=[CH:59][C:60]([C:63]3[CH:64]=[C:65]4[C:71]([C:72]5[CH:73]=[N:74][N:75]([CH2:77][C:78]6[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=6)[CH:76]=5)=[CH:70][NH:69][C:66]4=[N:67][CH:68]=3)=[CH:61][CH:62]=2)[CH2:53][CH2:52]1)=[O:50]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CN(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)CC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 97 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(dimethylamino)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) piperazin-1-yl)ethanone (80 mg, 0.115 mmol) was hydrolyzed with lithium hydroxide (25 mg, 0.578 mmol) in THF/methanol/water (5/1/1 mL) to yield 60 mg (80.0% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.826-8.822 (d, 1H), 8.605-8.601 (d, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.70-7.68 (d, 2H), 7.40-7.35 (q, 1H), 7.17-7.12 (m, 3H), 7.07-7.02 (m, 2H), 5.45 (s, 2H), 4.35 (s, 2H), 3.84-3.81 (t, 2H), 3.63-3.60 (t, 2H), 3.36-3.33 (t, 4H), 2.99 (s, 6H). MS: m/z=537.9 (M+1), HPLC: 91.53% in method A.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[K+].C(NC1N(C)C(=O)C2C(=C(B(O)O)C=CC=2)N=1)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:79]1[CH:80]=[C:81]2[C:86](=[O:87])[N:85]([CH2:88][C:89]3[CH:94]=[CH:93][C:92]([O:95][CH3:96])=[CH:91][C:90]=3[O:97][CH3:98])[CH2:84][CH2:83][N:82]2[CH:99]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:79]3[CH:80]=[C:81]4[C:86](=[O:87])[N:85]([CH2:88][C:89]5[CH:94]=[CH:93][C:92]([O:95][CH3:96])=[CH:91][C:90]=5[O:97][CH3:98])[CH2:84][CH2:83][N:82]4[CH:99]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2CCn3cc(Br)cc3C2=O)c(OC)c1
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCn3cc(-c4cccc5c(=O)n(C)c(NC(C)(C)C)nc45)cc3C2=O)c(OC)c1
Temperature: 110 °C
Yield: 19.4 %

Procedure:
A mixture of Pd(dppf)Cl2 DCM adduct (4.0 mg), 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (37 mg, 0.10 mmol), (BPin)2 (39.5 mg, 0.155 mmol) and KOAc (22 mg, 0.22 mmol) in 0.5 mL of DMF was heated in a microwave at 110° C. for 40 min. It was diluted with 15 mL of EtOAc and filtered through a pad of Celite. The filtrate was washed with 2 mL of water followed by 2 mL of brine. The organic solution was dried over Na2SO4 and concentrated. The dark residue containing (2-(tert-butylamino)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid (714) was used in next step without purification. m/z (ESI, +ve) 276.1 (M+H)+. A 5 mL glass microwave reaction tube was charged with the crude (2-(tert-butylamino)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid (714), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (2.86 mg, 6.00 μmol), Pd2(dba)3 (2.75 mg, 3.00 μmol), 7-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (36.5 mg, 0.10 mmol) and K3PO4 (63 mg, 0.30 mmol). The tube was purged with argon, and the contents were suspended in Dioxane (2 mL) and Water (0.50 mL). The reaction mixture was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 130° C. for 45 min. Additional X-Phos (3 mg) and Pd2(dba)3 (3 mg) were added and the resulting mixture was heated again in a microwave at 140° C. for 25 min. It was diluted with 10 mL of EtOAc, washed with 2 mL of 0.5 N NaOH followed by 2 mL of brine. The organic solution was concentrated and the residue was purified by silica gel chromatography (eluted with 40-65% EtOAc in Hexanes) to give 2-(tert-butylamino)-8-(2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-3-methylquinazolin-4(3H)-one (449a; 10 mg, 19% yield) as a brown amorphous solid. m/z (ESI, +ve) 516.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(CO)nc2cc(Cl)cnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.52 g of 6-chloro-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 64), 1.23 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.66 ml of tributylphosphine, 0.67 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.51 g of the title compound, melting at 82°-84° C. (softening).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][C:19]([F:21])([F:20])[CH:18]([F:22])[C:17]([F:24])([F:23])[F:16])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC(=O)Nc1cc(Cl)c(O)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 20 h

Procedure:
47 g of 4-acetylamino-2,5-dichlorophenol together with 154 g of 90% potassium hydroxide solution and 130 ml of dimethylformamide are stirred in an autoclave. 75.8 g of hexafluoropropylene are then pressed into the closed autoclave. The mixture is stirred for 20 hours at 70° C. under the pressure existing in the autoclave. After cooling, the mixture is concentrated by rotary evaporation and the residue is dissolved in methylene chloride. The resultant solution is washed with water, dried over Na2SO4 and concentrated. The crude product obtained as residue is chromatographed through a column of silica gel (length: 1 m; diameter: 10 cm) eluted with an 11:1 mixture of toluene and acetone, affording 4-acetylamino-2,5-dichloro-1-(1,1,2,3,3,3-hexafluoropropyloxy)benzene in the form of pale yellow crystals (m.p.: 93°-95° C.), 26 g of which are kept for 10 hours under reflux with 110 ml of ethanol and 35.6 ml of 37% hydrochloric acid. The reaction mixture is then concentrated, diluted with ice/water and made weakly alkaline. The product is extracted from the mixture with methylene chloride. The organic extract phase is washed with water, dried over Na2SO4 and concentrated. The residue is purified by distillation, thus affording the title compound of the formula ##STR12## as a colourless liquid with a boiling point of 81°-83° C./0.05 torr.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:29][CH2:30][C:31]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 420 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenylpropionyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:4][N:3]=1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25]>>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[O:4][N:3]=[C:2]([N:1]=[CH:22][O:23][CH2:24][CH3:25])[N:6]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)c1cc(-c2nc(N)no2)cc(C(C)(C)C)c1O
Product: CCOC=Nc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 67.5 %

Procedure:
A mixture of 0.87 g (0.003 mole) of 4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and 25 ml (22.3 g; 0.15 mole) of anhydrous triethyl orthoformate is stirred at reflux (under a nitrogen atmosphere) for 24 hours. The cooled mixture is evaporated, and the residue is distributed between 75 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted several times with fresh dichloromethane, and the combined organic layers are washed with brine. The organic layer is dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from aqueous acetonitrite yields 0.70 g (67% yield) of ethyl N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-3-yl]methanimidoate, mp 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[N:30]=[CH:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[N:30]=[CH:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-n1cnc(CBr)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cn(-c3ccccc3Cl)cn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
19 mg (0.06 mmol) of the compound from Example 5A were dissolved in 5 ml of acetonitrile, and 17 mg (0.13 mmol) of potassium carbonate and 17 mg (0.06 mmol) of the compound from Example 42A were added. The mixture was stirred at 65° C. for 2 h and then stirred at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 4 mg (12% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[F:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][C:11]=1[F:19]
Reactant: OB(O)c1ccc(Br)c(F)c1
Reactant: Nc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc(Br)c(F)c2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-bromopyrimidin-2-amine (2.1 g, 0.012 mol) in 1,4-dioxane (30 mL) was added (4-bromo-3-fluorophenyl)boronic acid (2.0 g, 0.0091 mol), potassium phosphate (6.4 g, 0.030 mol) and tetrakis(triphenylphosphine)palladium (700 mg, 0.6 mmol), water (5 mL). The solution was degassed with N2, and heated at 120° C. for 4 h. The mixture was cooled to RT, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-30%) to afford the desired compound. LCMS: (M+H)=267.9.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:10][O:11][CH:12]([O:29][CH3:30])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH2:27])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:30][O:29][CH:12]([O:11][CH3:10])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH:27][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1
Reactant: COC(OC)c1cc(-c2cccc(C(C)(C)N)c2)n(C)n1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)c1cc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
2,2,2-Trifluoroethylsulfonyl chloride (253 mg, 1.4 mmol) was added dropwise to a stirred solution of the amine from Step 2 (267 mg, 0.92 mmol) and Et3N (193 □L, 1.4 mmol) in CH2Cl2 (25 mL) at RT under N2. The mixture was stirred at RT for 30 min and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 mL) and concentrated under reduced pressure to yield the crude sulfonamide (213 mg, 53%). 1H NMR (CDCl3, 360 MHz) δ 7.60-7.53 (2H, m), 7.49 (1H, t, J=7.6 Hz), 7.37 (1H, d, J=7.6 Hz), 6.38 (1H, s), 5.50 (1H, s), 5.02 (1H, s), 3.88 (3H, s), 3.47 (2H, q, J=8.8 Hz), 3.44 (6H, s), 1.81 (6H, s). MS (ES+) C18H24F3N3O4S requires: 435, found: 404 (M-OCH3+, 100%).