Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:20]([O:22]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:3].C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.C(OC(C)=O)C>CO>[NH:1]1[C:20](=[O:22])[C@H:7]([CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:6][C:4](=[O:5])[C@@H:2]1[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC1=O
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Boc-L-Ala-L-Glu(OBzl)-ONp (56.0 g, 0.1 mol) was dissolved and cooled to −15° C. TFA was added and the mixture was stirred for 1 hour and gradually warmed to room temperature. Completion of the reaction was monitored by TLC using the system CHCl3:Et-OAc:MeOH=6:3:1. After completion of the reaction, the mixture was evaporated in vacuum, then twice evaporated with iso-propanol and dissolved in 500 ml of EtOAc. N-methylmorpholine was added until the mixture reached a pH level of 9 to 9.5. After 12 hours, the cyclo-L-Ala-L-Glu(OBzl) precipitated. The precipitate was filtered off, washed with EtOAc, ether and hexane. The yield was 21.0 g (70%). Rf=0.55 (CHCl3:EtOAc:MeOH:AcOH=6:3:1:0.1); HPLC data: retention time 15.9 min.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18](O)=[O:19])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([NH:55][CH2:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)=[O:19])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred mixture of 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid (0.13 g, 0.38 mmol), 1-hydroxybenzotriazole (0.077 g, 0.57 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.57 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.14 mmol) and 3-(aminomethyl)pyridine (0.04 mL, 0.39 mmol). The resulting reaction mixture was stirred for 18 h at ambient temperature, then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a colorless solid in 87% yield (0.14 g): mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.06-6.98 (m, 2H), 6.87 (s, 1H), 643 (t, J=5.6 Hz, 1H), 4.95 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.64 (d, JC-F=247.1 Hz), 162.6, 150.4, 149.3, 149.1, 140.8, 135.7, 134.5, 133.7, 132.3, 131.2 (d, JC-F=3.2 Hz), 130.3 (d, JC-F=8.3 Hz), 125.3, 123.7, 120.2, 115.8 (d, JC-F=21.6 Hz), 49.0, 41.5, 16.0; MS (ES+) m/z 424.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccccc1N
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3N)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)[N:9]=2)=[CH:4][CH:3]=1.O[N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.NC1C=CC=CC=1>O.C(N(CC)CC)C.CN(C)C=O>[C:35]1([NH:31][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:36]=[CH:37][CH:38]=[CH:39][CH:34]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(CCCC(=O)O)N=C2c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCC(=O)Nc1ccccc1)N=C2c1ccc(Cl)cc1
Yield: 49.4 %

Procedure:
(±)-4-(4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyric acid (0.50 g) and 1-hydroxybenzotriazole (0.17 g) are added to dry dimethylformamide (20 ml) and the mixture is stirred under ice-cooling. Thereto is added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.25 g), and then triethylamine (0.24 g) and aniline (0.11 g) are added. The mixture is stirred at room temperature for 4 days. After the completion of the reaction, water (100 ml) is added and the mixture is extracted with ethyl acetate. The organic layer is washed with 6N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=10:l) and crystallized from ethyl acetate and isopropyl ether to give 0.29 g of (±)-N-phenyl-4-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl)butaneamide as white powdery crystals, melting point 238°-240° C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH:37]3[CH2:42][CH2:41][N:40]([S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:45])=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:53][C@@H:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([S:43]([C:46]3[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=3)(=[O:45])=[O:44])[CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:24][O:23][C:22]1[CH:54]=[CH:55][C:19]([OH:18])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 38.3 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-{[4-({1-[(4-methylphenyl)sulfonyl]-4-piperidinyl}amino)phenethyl]amino}-2-propanol (0.130 g, 0.167 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.035 g, 0.064 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8][S:20][CH3:19])[CH:7]=1
Reactant: Fc1ccc(Oc2ncc(CBr)cc2Br)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
The product from Example 311c (0.75 g, 1.979 mmol) and sodium thiomethoxide (0.139 g, 1.979 mmol) were combined in dimethylformamide (3.96 mL), stirred for 4 hours at ambient temperature, and partitioned into ethyl acetate and cold water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated to afford the title compound (0.66 g, 96%).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1.C>[OH-].[Na+]>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:18][C:1](=[O:8])[C:2](=[O:4])[NH:19]2
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(F)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (17.4 g, 0.100 mol) and 4-fluoro-1,2-diaminobenzene (1.00 g, 7.93 mmol) was heated to reflux with stirring under N2 for 2 h. The reaction was cooled to room temperature and the solid was collected by vacuum filtration and rinsed with EtOH (50 mL) to give a gray-brown solid which was further dried under vacuum (0.1 torr, 25° C.) to yield 1.06 g (74.4%) which was >98% pure by NMR. An analytically pure sample was prepared by dissolution of 60 mg of the solid in 1.0N NaOH and treatment of this solution with activated charcoal. Filtration of this mixture through a pad of Celite and acidification with 1N HCl gave fine white needles which were collected by vacuum filtration, rinsed with H2O and further dried under vacuum (0.1 torr, 25° C.) to give 25.5 mg of white needles, mp 375°-380° C. (dec) (lit. >300° C. (Sarges, R., et al., J. Med. Chem. 33:2240 (1990)). 1H NMR (d6 -DMSO) δ6.90 (m, 2H, ArH), 7.09 (dd, J=9, J=5.4), 11.9 (s, 1H, NH), 11.96 (s, 1H, NH). EIMS m/z180(100,M+), 152(44), 124(63), 97(43), 28(53). EIHRMS calc. for C8H5FN2N2O2 180.0334, found 180.0337.
Reaction SMILES: [N+](C1C=C(S(CC[O:15][C:16](=[O:63])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:62])[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[C:29]([S:33]([N:36]3[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=[C:37]3[S:45]([CH2:47][C:48]3[C:53]([CH3:54])=[C:52]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])[CH:51]=[CH:50][N:49]=3)=[O:46])(=[O:35])=[O:34])=[C:28]([CH3:61])[CH:27]=2)(=O)=O)C=CC=1)([O-])=O.C([O-])(O)=O.[Na+:68]>C1COCC1.O>[Na+:68].[CH3:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([CH3:61])[C:29]=1[S:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[S:45]([CH2:47][C:48]1[C:53]([CH3:54])=[C:52]([O:55][CH2:56][C:57]([F:58])([F:59])[F:60])[CH:51]=[CH:50][N:49]=1)=[O:46])(=[O:35])=[O:34])[O:25][CH2:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([O-:63])=[O:15])=[O:62]
Reactant: Cc1cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)NCCCCCC(=O)[O-])cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Yield: 50.6 %

Procedure:
A solution of 6-[2-(3,5-dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimdazole-1-sulfonyl}phenoxy)acetylamino]hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 18, 420 mg, 0.45 mmol) and of NaHCO3 (42 mg, 0.49 mmol) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 1 h. Then volatile materials were removed, the residual gummy oil was dissolved in CH2Cl2 and the mixture was filtered to remove un-dissolved solid. The filtrate was concentrated to dryness and the residual semi-solid was treated with diethyl ether to precipitate a solid which was briefly treated with CH3CN. The solid was collected from CH3CN suspension by filtration to give Compound 6 (170 mg 50%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.S(Cl)([Cl:26])=O>>[O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:26])=[O:20])=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Product: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (90 ml) was added to 4-(3-oxo-1,3-dihydro-2H-pyrazolo-[4,3-c]cinnolin-2-yl)benzoic acid (2.36 g, 7.70 mmol). The mixture was heated to reflux for 2 h under nitrogen atmosphere. A dark red solution was obtained, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (30 ml) was added to the residues and the mixture was stirred at room temperature under nitrogen atmosphere until precipitation was complete. The solids were collected by filtration and washed with toluene (2×30 ml). The title compound was isolated as a red solid (2.20 g, 6.77 mmol, 88%) LCMS: m/z 321 [M+H]+ (methyl ester resulting from sample make-up in methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[C:32]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:30][N:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:30][N:29]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=2)[CH:5]=1
Reactant: Cc1cc(N)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reactant: CC(=O)c1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)c1ccnc(Nc2cc(C)cc(-c3cnc(C(C)(O)C(F)(F)F)s3)c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To Intermediate 17 (500 mg, 1.654 mmol) in a scintillation vial was added dioxane (8.27 mL), cesium carbonate (1078 mg, 3.31 mmol), and 1-(2-chloropyrimidin-4-yl)ethanone (285 mg, 1.819 mmol). The system was purged and flushed with Ar(g) three times before adding Xantphos (144 mg, 0.248 mmol) and Pd(OAc)2 (40.8 mg, 0.182 mmol). The system was purged and flushed with Ar(g) three times before sealing the system and heating to 100° C. The reaction was stirred overnight and was cooled to room temperature. The reaction mixture was filtered through celite (washed with chloroform) and diluted with water. The organic layer was separated, dried over sodium sulfate, and was concentrated to dryness before purification by column chromatography (10-40% acetone in hexanes, linear gradient) to yield 1-[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]ethanone (250 mg, 0.592 mmol, 36%). MS ESI: [M+H]+ m/z 423.1. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.9, 1H), 7.95 (s, 2H), 7.34 (dd, J=8.1, 13.0, 3H), 7.10 (s, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 1.85 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)#[CH:36]>O1CCCC1.C(OCC)(=O)C.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.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:36]#[C:35][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Yield: 60.4 %

Procedure:
A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1; 440 mg, 1.35 mmol), DBU (1230 mg, 8.08 mmol) and ethynylbenzene (413 mgs, 4.04 mmol) in tetrahydrofuran (5 ml) to produce an orange solution. The mixture was purged with nitrogen and dichlorobis(triphenylphosphine)palladium(II) (47.3 mg, 0.067 mmol) and copper(I) iodide (25.6 mg, 0.135 mmol) were added before the whole was subjected to microwave radiation for 1 hour at 80° C. Upon cooling, the resulting mixture was diluted with ethyl acetate and washed with brine and the organic layer was purified by silica chromatography (eluting with 0-30% ethyl acetate-petrol) to yield 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (320 mg, 0.815 mmol, 61% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=2)=[O:10])=[CH:24][CH:23]=1
Reactant: Cn1cc(C(=O)Nc2ccccc2Br)c(C(F)(F)F)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(Cl)cc2)c(C(F)(F)F)n1

Procedure:
A solution of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid(2-bromo-phenyl)amide (0.64 g), 4-chlorobenzene boronic acid (0.29 g), powdered sodium carbonate (0.25 g) and tetrakis(triphenylphosphine) palladium (0.04 g) in 25 ml 1,2-dimethoxyethane (DME) and 2 ml water is heated at reflux temperature for 20 hours. After cooling, the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate/water. The ethylacetate phase is washed twice with water and brine and then dried over sodium sulfate. Distilling off the solvent left the raw material which can be further purified by column chromatography (silicagel; eluant: ethylacetate/hexane 1:1) or recrystallization from TBME/hexane. The yield after purification is 0.6 g; m.p.=145–146° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:21][CH2:22]1
Reactant: CCC(Br)CC
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(C(CC)CC)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 3-bromopentane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13](=[O:15])[NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH3:12])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Cool a solution of 3-((S)-1-carboxy-ethoxy)-benzoic acid methyl ester (0.32 g, 1.43 mmol) in pyridine (5 mL) to 0° C. and add 4-aminobenzonitrile (0.20 g 1.69 mmol) followed by phosphorous oxychloride (0.15 mL, 1.60 mmol). Stir the mixture at 0° C. for 1 hour then dilute with water and extract with EtOAc. Wash the combined organic portion with a 2N solution of hydrochloric acid then dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.42 g of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester as a foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:15].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:15]
Reactant: Oc1ccc(OCCCCBr)cc1
Reactant: CCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 6.9 %

Procedure:
To a solution of compound 12a (250 mg, 1.02 mmol) and N-ethylaniline (0.24 mL, 2.04 mmol) in acetonitrile (5.0 mL), diisopropylethylamine (0.42 mL, 3.05 mmol) was added dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 12 as a colorless oil (20 mg, 0.07 mmol, 12% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 286.18. 1H NMR (400 MHz, Chloroform-d) δ 7.23 (t, J=8 Hz, 1H), 6.65-6.81 (m, 8H), 4.71 (bs, 1H), 3.95 (t, J=5.2 Hz, 2H), 3.33-3.52 (m, 4H), 1.27-1.33 (m, 4H), 1.17 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[C:16]([O:15][C@H:13]2[CH2:14][C@@H:9]([OH:8])[CH2:10][CH2:11][C@@H:12]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([N:26]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3C[C@@H](O)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 100.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1S*,2R*,5S*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (174 mg, 0.233 mmol) prepared in Example 163g, tetrabutyl ammonium fluoride (1.0 M solution in THF; 0.466 mL, 0.466 mmol) and THF (5.0 mL), to yield the title compound (148 mg, 93%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=CC(C(O)=O)=C[C:3]=1O.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[CH:2]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[C:13]([OH:12])[CH:14]=[N:15][CH:16]=1)([CH3:10])[CH3:3]
Reactant: O=C(O)c1cncc(O)c1
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Product: CC(C)OC(=O)c1cncc(O)c1

Procedure:
The title compound was synthesized by substituting 4-chloro-3-hydroxybenzoic acid in Example 116A with 5-hydroxy-nicotinic acid. MS (DCI) m/z 182(M+H)+.