Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([S:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)[O:26][C:27]([CH3:30])(C)C)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:33]([O:36]CC)(=[O:35])[CH3:34].Cl.C(=O)([O-])[OH:41].[Na+]>C(OCC)(=O)C>[C:27]([OH:26])(=[O:41])/[CH:30]=[CH:34]/[C:33]([OH:36])=[O:35].[CH3:25][NH:24][CH2:23][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Reactant: CN(Cc1cc(-c2ccc(C#N)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Product: CNCc1cc(-c2ccc(C#N)cc2)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 3 h

Procedure:
To a solution (2 mL) of tert-butyl {[5-(4-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (382 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) at room temperature. The mixture was stirred for 3 hr, and basified with a saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (2 mL) of fumaric acid (77.1 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 218 mg, 55%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[C:16]([Cl:22])[CH:15]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][NH2:13])=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:56]1([C:59](O)=[O:60])[CH2:58][CH2:57]1>C(Cl)Cl.O>[F:24][C:2]([F:1])([F:23])[CH:3]([C:14]1[CH:15]=[C:16]([Cl:22])[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][NH:13][C:59]([CH:56]2[CH2:58][CH2:57]2)=[O:60])=[CH:8][CH:7]=1
Reactant: NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Cl2 (5 mL) was added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with CHCl3 (35 mL) The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:18][C:11]1[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[S:14][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(N)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a two necked 250 mL round bottom flask, charged with 1-[5-(2,4-Dichlorophenylsulfanyl)-4-nitro-2-thienyl]ethanone (7.0 g, 20.2 mmol) prepared as in example 2, 50 mL ethanol and 50 mL of water followed by ammonium chloride (4.32 g, 80.8 mmol) and iron powder (4.53 g, 80.8 mmol). The resulting reaction mixture was heated at 80° C. for 2 hours. After this time, the reaction mixture was cooled to ambient temperature and was passed through a cellite cartridge. The filtrate was concentrated and water was added to the residue and extracted with ethyl acetate. The combined organic layer was separated, dried (Na2SO4), filtered and concentrated to afford the title product (6.4 g, 78% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.64 (1H, s), 7.44 (1H, s), 7.37 (1H, m), 6.68 (1H, m), 2.50 (3H, s).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:54])([C:50]([F:53])([F:52])[F:51])[C:24]([F:49])([F:48])[C:25]([F:47])([F:46])[O:26][C:27]([F:45])([F:44])[C:28]([F:43])([F:42])[O:29][C:30]([F:41])([F:40])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([O:29][C:28]([F:42])([F:43])[C:27]([F:44])([F:45])[O:26][C:25]([F:46])([F:47])[C:24]([F:48])([F:49])[C:23]([F:22])([F:54])[C:50]([F:52])([F:53])[F:51])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.01 g, 3.55 mmol) and 6-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromohexane (2.4 g, 4.03 mmol; prepared by combining 1,6-dibromohexane and 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 1 vol. % ethyl acetate/toluene
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14](C4C=CC=CC=4)[C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:24]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:33]([O:35][C:36](=[O:37])[C:26]=2[CH:25]=1)=O>>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:33](=[O:35])[C:27]2[C:26](=[CH:25][CH:24]=[C:29]([C:30]([OH:32])=[O:31])[CH:28]=2)[C:36]1=[O:37]
Reactant: Cc1ccc(-c2nc3c(-c4ccccc4)cccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: Cc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methylphenyl)-4-phenylbenzoxazole (167 mg, 0.9 mmol) and 1,2,4-benzenetricarboxylic anhydride (250 mg, 0.9 mmol) the title compound was obtained, 340 mg (82%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.34(d, 2H), 8.26(dd, 1H), 8.13(d, 1H), 8.05(d, 1H), 7.85(d, 1H), 7.73(m, 4H), 7.50(t, 1H), 7.39(t, 1H), 2.28(s, 3H). MS 473 m/z (M−H)−.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.CN.[C:29]([BH3-])#[N:30].[Na+].Cl>CO>[CH2:3]([N:4]1[CH2:5][CH2:6][C@:7]23[C:8]4[C:13]5[O:14][C@H:15]2[C@@H:16]([NH:30][CH3:29])[CH2:18][CH2:19][C@@:20]3([OH:23])[C@H:21]1[CH2:22][C:9]=4[CH:10]=[CH:11][C:12]=5[OH:24])[CH:2]=[CH2:1].[CH2:3]([N:4]1[CH2:5][CH2:6][C@:7]23[C:8]4[C:13]5[O:14][C@@H:15]2[CH:16]([NH:30][CH3:29])[CH2:18][CH2:19][C@@:20]3([OH:23])[C@H:21]1[CH2:22][C:9]=4[CH:10]=[CH:11][C:12]=5[OH:24])[CH:2]=[CH2:1]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@@H]2C(NC)CC[C@@]3(O)[C@H]1C5
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](NC)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 17 h
Yield: 12 %
Yield: 24 %

Procedure:
Naloxone hydrochloride (3.0 g), methylamine hydrochloride (5.57 g) and sodium cyanoborohydride (0.33 g) were suspended in anhydrous methanol (40 ml) and stirred for 17 hours at room temperature. After addition of concentrated hydrochloric acid (1.0 ml) and removal of solvent by distillation, distilled water (50 ml) was added followed by washing with chloroform (20 ml). Saturated aqueous sodium bicarbonate (10 ml) was added to make the solution basic followed by extraction with chloroform (30 ml×3). After drying with anhydrous magnesium sulfate, the solvent was distilled off. The resulting crude product was purified with silica gel column chromatography (Merk 7734 100 g; ethyl acetate/methanol/aqueous ammonia=90/10/1→80/20/2) to obtain the target compound in the form of a pure fraction (12 0.4 g, 12%; 13 0.8 g, 24%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.[F:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[O:43][CH2:42][CH2:41][CH:40]2[NH2:47]>ClCCl>[F:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[O:43][CH2:42][CH2:41][CH:40]2[NH:47][C:21](=[O:22])[CH2:20][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: NC1CCOc2ccc(F)cc21
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)NC1CCOc2ccc(F)cc21
Reaction time: 60 h

Procedure:
A solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.063 g, 0.204 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.059 g, 0.305 mmol) and 6-fluorochroman-4-amine (0.037 g, 0.224 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring for approximately 60 hours, the reaction was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.22-7.31 (m, 2H), 7.15-7.22 (m, 5H), 7.05-7.10 (m, 2H), 6.85-6.94 (m, 3H), 6.75-6.81 (m, 1H), 5.13 (dt, J=8.5, 5.8 Hz, 2H), 4.18 (d, J=14.6 Hz, 1H), 4.10-4.21 (m, 1H), 3.97-4.09 (m, 1H), 4.01 (d, J=14.6 Hz, 1H), 3.54-3.62 (m, 2H), 2.54-2.64 (m, 2H), 2.12-2.25 (m, 1H), 1.91-2.02 (m, 1H), 1.81-1.90 (m, 2H); MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Cl:19][C:20]1[C:29]([CH2:30]Br)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[Cl:19][C:20]1[C:29]([CH2:30][O:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(COc2ccnn2C)c1Cl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
4.3 g (44 mmol) of 1-methyl-5-hydroxypyrazol, 9.1 g of potassium carbonate and 100 ml of tetrahydrofurane are heated at 65° C. for 1 h. 15 g (44 mmol) of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate and 150 ml of tetrahydrofurane are added to this mixture and heated at 40° C. for 4 h. This mixture is stirred for 12 h, freed from the solvent under reduced pressure, taken up in ethyl acetate, washed with sodium bicarbonate solution and water, dried and freed form the solvent. The crude product is purified over silica gel (eluent: cyclohexane/ethyl acetate=1/1). Yield: 7.6 g; m.p. 70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:24]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:24]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2)(=[O:40])=[O:39]
Reactant: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NS(C)(=O)=O)ccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (EXAMPLE 41, 300 mg) in dry methylene chloride (6 ml) under nitrogen is added pyridine (119 μl) and methanesulfonyl chloride (57 μl). The mixture is stirred at 20°-25° for 24 hr and then diluted with methylene chloride (20 ml) and water (8 ml). The layers are separated and the organic phase is washed with saline (8 ml), dried over sodium sulfate, and concentrated to give a solid which is then chromatographed on silica gel (230-400 mesh, 34 g, 5-6 psi), eluting with methanol/chloroform (2.5/97.5). Pooling of the appropriate fractions, concentration to a solid, and recrystallization from chloroform gives the title compound, mp 232°-233° (decomp).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[C:29](=[O:32])([O-])[O-:30].[Cs+].[Cs+].Br.Br[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>CS(C)=O>[F:21][C:20]([F:23])([F:22])[C:29]([OH:30])=[O:32].[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][O:30][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: O=C([O-])[O-]
Reactant: BrCc1cccnc1
Agent: Br
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccc(OOCc3cccnc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Product: O=C(O)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(100 mg, 0.252 mmol) in DMSO (1 ml) was added cesium carbonate (166 mg, 0.509 mmol) and then 3-(bromomethyl)pyridine hydrobromide (89 mg, 0.352 mmol, Aldrich) at ambient temperature under nitrogen. The resulting yellow suspension was stirred for 3 h. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a TFA modifier (Method C). The solvent was evaporated in vacuo to give the title compound (65 mg) as a yellow solid; LCMS: (System 4) MH+=489, tRET=2.25 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-chlorobenzoate (2.5 g, 13.3 mmol) is added to a solution of 2.5 g (8.84 mmol) of the title B compound, 4-benzyloxybenzenesulfonyl chloride in 50 mL of DCM, then 1.4 g (1.43 mL, 17.68 mmol) of pyridine is added. The mixture is stirred overnight at RT. The organic solution is then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to a slightly red solid. The solid is adsorbed on 13 g of silica gel and chromatographed (FlashElute 40M silica gel column) using 1 L of an EtOAc (15%)-hexane (85%) mixture as the eluent, followed by 1 L of DCM to afford 2-(4-benzyloxybenzene-sulfonylamino)-4-chloro-benzoic acid methyl ester as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccccc1Cl
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2Cl)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68.2 mg, 0.3 mmol) was converted, using 2-chlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (11 mg, 10%) which was obtained as an off-white solid. MS: m/e=336.5 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CC[O:36]CC1.CN(C(ON1N=[N:54][C:49]2C=[CH:51][CH:52]=[N:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:52]([NH:53][C:48](=[O:36])[CH2:49][NH:54][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:51]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 23 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.061 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.041 mL, 0.369 mmol), ethanamine, HCl (9.02 mg, 0.111 mmol), and HATU (42.0 mg, 0.111 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.6 min) to give (R/S)-N-(2-(ethylamino)-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8.6 mg, 0.014 mmol, 23.60% yield): LCMS=516.2[M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.36 Hz), 7.65-7.78 (4 H, m), 7.53-7.65 (3 H, m), 5.20 (1 H, s), 3.81-3.96 (2 H, m), 3.23 (2 H, q, J=7.26 Hz), 1.07-1.14 (3 H, m). HPLC Peak RT=9.5 min (Analytical Method D).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[F:30])[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[F:30])[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1ccc(F)c(Cl)c1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccc(F)c(Cl)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 5.3 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(3-chloro-4-fluorophenoxy)ethylamine hydrochloride (824 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(3-chloro-4-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (26 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C1COCC1>[Br:45][CH2:23][CH2:22][CH:20]1[CH2:19][CH2:18][C:17]2[C:10]3[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:15][C:16]=2[CH2:21]1
Reactant: OCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of THF (20 mL) was added 0.63 (102, 1.56 mmol, 1 equiv) of 2-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol, 0.82 g (3.12 mmol, 2 equiv) triphenylphosphine and 1.03 g (3.12 mmol, 2 equiv) carbon tetrabromide. The solution was stirred at rt for 1 h until completion and the reaction mixture was evaporated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with 9:1 CH2Cl2/EtOAc yielding 396 mg (54%) of a light yellow solid. 1H-NMR (CDCl3-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.58 (m, 1H), 7.24 (m, 2H), 7.10 (s, 1H), 3.56 (m, 2H), 3.15 (m, 2H), 3.03 (m, 1H), 2.57 (m, 1H), 2.19 (m, 2H), 2.04 (m, 2H), 1.68 (m, 1H); TLC Rf=0.30 (9:1 CH2Cl2/EtOAc); LCMS RT=3.92 min; [M+H]+=466.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.O>[N:37]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:3][C:2]=1[Cl:1])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CO)c(Cl)c4)ccc3=O)ccnc2c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 6-(3-chloro-4-(hydroxymethyl)phenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1060 mg, 2421 μmol) and TEA (337 μL, 2421 μmol) in DCM (10 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (187 μL, 2421 μmol) in DCM (1 mL). After 3 hours, the mixture was partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was further extracted with DCM (2×10 mL). The combined organics were dried over MgSO4, then concentrated to a solid. Solid was then dissolved in DMF (5 mL) and sodium azide (787 mg, 12104 μmol) in water (5 mL) was then added. The biphasic solution was then heated to 60° C. overnight. The reaction was then partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was then further extracted with DCM (2×10 mL). The combined organics were then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 1 to 4% of MeOH/DCM. MS (ESI pos. ion) m/z: 463 (MH+); calc'd for C23H19ClN6O3: 462.