Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[NH:24][C:23](=[O:38])[N:22]=2)=[CH:17][C:14]=1[C:15]#[N:16]>CN(C=O)C>[NH2:16][C:15]1[C:14]2[CH:17]=[C:18]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[NH:24][C:23](=[O:38])[N:22]=3)[CH:19]=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)nc(=O)[nH]1
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1-c1cc(-c2ccc3onc(N)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
To a solution of acetohydroxamic acid (53 mg, 0.7 mmol) in DMF (5 mL) was added potassium tert-butoxide (80 mg, 1.76 mmol). The mixture was stirred at room temperature for 20 min, followed by the addition of solution of 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzonitrile (100 mg, 0.27 mmol) (Example 1, Step 4) in DMF (4 mL). The reaction was stirred at room temperature for 16 h. The mixture was quenched by acid and the product was purified by Prep-HPLC to give 75 mg (74%) of 4-(3-amino-1,2-benzisoxazol-5-yl)-6-{2-[(2-methylpropyl)oxy]phenyl}pyrimidin-2(1H)-one. 1H NMR (400 MHz, d6-DMSO): δ 11.80 (s, br, 2H), 8.78 (s, 1H), 8.37 (d, 1H), 7.66-7.45 (m, 3H), 7.24-7.00 (m, 3H), 6.60 (s, 2H), 3.83 (d, 2H), 2.05-1.97 (m, 1H), 0.98 (d, 6H). MS (EI) for C21H20N4O3: 377 (MH+).
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1
Reactant: CC1(C)CCC(C)(C)C(C)(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1=CC(C)(C)CCC1(C)C
Yield: 78.2 %

Procedure:
22.6 g of 1,2,2,5,5-pentamethylcyclohexanol are dissolved in 280 ml of benzene and, after the addition of 100 mg of p-toluenesulphonic acid, the mixture is boiled on a water separator for 7 hours. After cooling the solution, some solid sodium carbonate is added thereto, the mixture is filtered and the filtrate is evaporated at normal pressure. The residue is distilled in a water-jet vacuum. There are obtained 15.8 g of 1,3,3,6,6-pentamethylcyclohexen as a colorless liquid, b.p. 56°-57° C./17 mm.
Reaction SMILES: [H][H].[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3.CO.[OH-].[K+]>C(O)C.[Pd]>[F:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: [H][H]
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](F)C[C@@H]12

Procedure:
250 mg of 16βfluoro-5-α-androsten-17-one in 50 ml of ethanol was treated with 50 mg of 5% palladium on carbon and hydrogen gas for 21/2 hours. The reaction mixture, as indicated by the IR, is compatible with 16β-fluoro-5α-androstan-17-one. This crude product was treated with 5 ml methanol and 5 ml of 1N methanolic KOH for one hour. The mixture was partitioned between methylene chloride and water and subjected to HPLC as indicated above. Crystallization of the less mobile component from methanol gave 30 mg of 16α-fluoro-5α-androstan-17-one as prismatic needles, melting point 148°-150° C.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:18]([C:21]1[S:22][C:23]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:24]([CH3:26])[N:25]=1)=[N+:19]=[N-:20]>>[CH2:30]([NH:29][C:27]([C:23]1[S:22][C:21]([N:18]2[CH:17]=[C:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:20]=[N:19]2)=[N:25][C:24]=1[CH3:26])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C#CCc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(Cc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-phenyl-1-propyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 69% yield: mp 139-141° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.35-7.28 (m, 10H), 6.29 (br s, 1H), 4.60 (t, J=6.0 Hz, 2H), 4.13 (s, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.5, 153.2, 149.1, 137.9, 137.5, 128.9, 128.8, 128.7, 127.8, 126.8, 124.1, 119.2, 44.3, 32.1, 17.3; MS (ES+) m/z 390.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[NH2:20])C>N1C=CC=CC=1.[OH-].[Na+]>[CH2:1]([N:3]1[C:9](=[O:8])[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[C:15]=2[O:16][CH3:17])[NH:20][C:4]1=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To ethyl isocyanate (1.65 ml, 1.48 g, 20.8 mM) in pyridine (9.2 ml) at 0° C. was added a cold solution of 2-amino-5,6-dimethoxybenzoic acid ethyl ester (3.0 g, 20.8 mM) in pyridine (16.7 ml). The solution was stirred at 0° C. for thirty minutes, then kept at room temperature for one hour. During this time, a precipitate formed. The mixture was concentrated to dryness to give an off-white solid. This was dissolved in 69.9 ml of 1N NaOH (4:1 MeOH-H2O) and heated at reflux for two hours. The solvent was removed in vacuo and the residue dissolved in H2O (150 ml). The mixture was taken to pH 6 with acetic acid and the resulting white solid filtered, washed with H2O (50 ml), and dried to give crude product as a white solid; 3.12 g; mp 208°-211° C. Recrystallization from isopropanol (100 ml) and drying afforded the title compound as a white solid; 2.09 g; mp 212°-214° C., total yield 80.5%, CF3COOH(TMS), 7.60 (d, 1H, J7,8 =9.0 Hz, 7-H), 7.13 (d, 1H, J8,7 =9.0 Hz, 8-H), 4.20 (9, 2H, J=6.0 Hz, 9-H), 4.19 (s, 3H, 5 or 6-OCH3), 4.05 (s, 3H, 5 or 6-OCH3), 1.40 (t, 3H, J=6.0 Hz, 10-H). M+ 250.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.O(C1C=CC([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[O:10]([C:4]1[CH:3]=[CH:2][C:9]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[CH:8][C:5]=1[CH:6]=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(C=O)c2)OC1(C)C

Procedure:
The title compound was prepared in a 62% from 4-bromo-2-phenoxybenzaldehyde in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.43(s, 1H), 8.14(s, 1H), 7.89(d, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 6.88(d, 1H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02min.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[C:25](Cl)=[CH:24][C:21]([NH:22][CH3:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[C:25]([N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4]2)=[CH:24][C:21]([NH:22][CH3:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3-(Trifluoromethyl)piperidine (0.69 g, 4.5 mmol) followed by potassium carbonate (1.25 g, 9.1 mmol) were added to 4,5-dichloro-N-methyl-2-nitroaniline (1.00 g, 4.5 mmol) in DMF (15 mL). The reaction mixture was stirred 5 h at 80° C. and overnight at 70° C. After addition of further 1.5 eq of potassium carbonate the mixture was stirred 2 h at rt and 2 days at 100° C. The reaction mixture was filtered through a pad of ALOX B and concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12].ClCCOCCOCCOC.O[C:25]1[CH:32]=C[CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>>[O:11]([C:12]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:32]=1)[CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=Cc1ccccc1O
Reactant: COCCOCCOCCOC
Agent: COCCOCCOCCCl
Product: COCCOCCOCCOc1ccc(C=O)cc1
Yield: 70 %

Procedure:
The bisacrylamide triethylene glycol acetal crosslinker (606) or triglyme crosslinker as shown in FIG. 6 was synthesized in four steps on a multigram scale. The first step involved the preparation of 1-chloro-3,6,9-trioxadecane (603) using the procedure of Loth, H. & Ulrich, F. (1998) J. Control Release. 54, 273. Compound 603 was then used to alkylate hydroxy benzaldehyde (605) and produce p-(1,4,7,10-Tetraoxaundecyl)benzaldehyde (604). Compound 603 was chosen as the alkylating agent since it can be easily synthesized on a large scale (100 grams) enabling the preparation of 4 on a 20 gram scale (70% yield), using potassium carbonate as the base and 18-crown-6 as the phase transfer catalyst. Hydroxy-benzaldehyde could also be alkylated using 1-tosyl-3,6,9-trioxadecane and 1-bromo-3,6,9-trioxadecane but these approaches were discontinued because significantly lower yields of the desired product were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)cs1
Yield: 86.7 %

Procedure:
20.3 g (181 mmol) of 3-thiophenealdehyde, 50 ml of ethylene glycol and 2.00 g (7.96 mmol) of PPTS were dissolved in 230 ml of toluene, and dehydration was carried out using Dean-stark. After completion of the reaction, the mixture was extracted with ethyl acetate. The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to silica gel (ethyl acetate:hexane=1:10), to give 12.1 g (77.3 mmol, 86.7%) of the title compound as a yellow oil.
Reaction SMILES: C(C1C=C(C(N)C)C=CC=1C1C=C(F)C=CC=1OC)C=C.CC1C(O)=C(C)C=C(C(C)=O)C=1.C(C1C=C(C(NS(C2C=CC(F)=C(F)C=2)(=O)=O)C)C=CC=1C1C=C(F)C=CC=1OC)C=C.[F:66][C:67]1[CH:68]=[CH:69][C:70]([O:84][CH3:85])=[C:71]([C:73]2[C:78]([CH3:79])=[CH:77][C:76]([CH:80]([NH2:82])[CH3:81])=[CH:75][C:74]=2[CH3:83])[CH:72]=1.[CH3:86][C:87]1[C:91]([S:92](Cl)(=[O:94])=[O:93])=[C:90]([CH3:96])[O:89][N:88]=1>>[F:66][C:67]1[CH:68]=[CH:69][C:70]([O:84][CH3:85])=[C:71]([C:73]2[C:78]([CH3:79])=[CH:77][C:76]([CH:80]([NH2:82])[CH3:81])=[CH:75][C:74]=2[CH3:83])[CH:72]=1.[F:66][C:67]1[CH:68]=[CH:69][C:70]([O:84][CH3:85])=[C:71]([C:73]2[C:78]([CH3:79])=[CH:77][C:76]([CH:80]([NH:82][S:92]([C:91]3[C:87]([CH3:86])=[N:88][O:89][C:90]=3[CH3:96])(=[O:94])=[O:93])[CH3:81])=[CH:75][C:74]=2[CH3:83])[CH:72]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC
Agent: C=CCc1cc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)ccc1-c1cc(F)ccc1OC
Agent: CC(=O)c1cc(C)c(O)c(C)c1
Product: COc1ccc(F)cc1-c1c(C)cc(C(C)NS(=O)(=O)c2c(C)noc2C)cc1C

Procedure:
1-(5′-Fluoro-2′-methoxy-2,6-dimethyl-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 3,5-dimethyl-4-hydroxy acetophenone instead of 3′-allyl-4′-hydroxyacetophenone. The title compound was prepared in a similar manner to N-[1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 1-(5′-fluoro-2′-methoxy-2,6-dimethyl-biphenyl-4-yl)-ethylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 433.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1.[C:30](Cl)(=[O:32])[CH3:31].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCNC2)nc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCN(C(C)=O)C2)nc1
Reaction time: 0.08 h

Procedure:
To a solution of 2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-3-(piperidin-3-yl)-1,5-naphthyridine (RR3) (12 mg, 0.03 mmol) in DMF (0.3 mL) was added acetyl chloride (0.006 mL, 0.09 mmol) and Hunig's Base (0.015 mL, 0.09 mmol). After five minutes, the mixture was purified directly by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.78 (s, 1 H), 8.13 (s, 3 H), 7.64 (s, 1 H), 7.26 (m, 2 H), 4.50 (m, 2 H), 4.26 (brs, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 2 H), 3.08 (m, 2 H), 2.27 (m, 2 H), 2.24-2.19 (m, 1 H), 2.05 (s, 3 H), 1.80 (s, 1 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 433.2228 found, 433.2234 required.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH3:21]>C(O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH2:21])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOc1c(NCCP(=O)(OCC)OCC)c(=O)c1=O
Reactant: N
Solvent: CCO
Product: CCOP(=O)(CCNc1c(N)c(=O)c1=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester (1.69 g, 5.5 mmol) in 100% ethanol (40 mL) was placed in flask equipped with an addition funnel and a nitrogen inlet. Saturated ethanolic ammonia (190 mL) was placed in the addition funnel and added dropwise over 1 hour. The reaction mixture was left stirring at room temperature for a total of 24 hours and then concentrated in vacuo. The resulting solid was recrystallized from methanol in ethyl acetate to afford [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester as a yellow solid (1.27 g, 82%, mp=150°-152° C. dec); IR (KBr, cm-1): 1805, 1650; MS (+FAB): 277 (MH+, 100), 182 (20), 109 (15); 1H NMR (DMSO, 400 MHz): δ 7.5 (br s, 3 NH), 4.1-3.9 (m, 4H), 3.7-3.6 (m, 2H), 2.11 (d of t, J=17.5 and 7.5 Hz, 2H), 1.22 (t, 6H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3Cl)cc21

Procedure:
Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 2-chlorophenyl boronic acid. White solid: mp 181-182° C.; MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calc. For C16H14CINO2: C, 66.79, H, 4.90, N, 4.87. Found: C, 66.78, H, 4.82, N, 4.55
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH:12]=[CH:11][NH:10][C:9]1=[S:13])=[O:7])[CH2:2][CH2:3][CH3:4].BrBr.C(N(CC)CC)C>ClCCl>[CH2:1]([N:5]1[C:6](=[O:7])[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1cc[nH]c1=S
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1sc2nccn2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To solution containing 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione (4.73 g, 23.7 mmole) suspended in 15 mL of dichloromethane cooled to 0° C. under a nitrogen atmosphere, was added bromine (3.79 g, 23.7 mmole) dissolved in 15 mL of dichloromethane, in a dropwise manner. After the addition was complete, triethylamine (4.81 g, 47.5 mmole) dissolved in 15 mL dichloromethane was added such that the temperature of the reaction mixture never exceeded 0° C. The reaction mixture was maintained at 0° C. for an additional 2 h and then stirred for 16 h at room temperature. It was then diluted with 150 mL of dichloromethane and washed twice with water and once with a saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate and evaporated to dryness to yield 4.30 g (92%) of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one as an off-white powder: mp 142°-143° C.; 1H NMR (CDCl3) δ7.40 (d, 1H), 7.20 (d, 1H), 3.79 (t, 2H), 1.73 (m, 2H), 1.40 (m, 2H), 0.957 (t, 3H) ppm; IR (KBr) ν1702 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N+:3]=1[O-].O.P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[C:4]([Cl:22])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(c1ccc(Cl)[n+]([O-])c1)c1ccccc1F
Solvent: O
Product: O=S(=O)(c1ccccc1F)c1ccc(Cl)nc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine 1-oxide from Step 1 (0.27 g, 0.938 mmol) was suspended in phosphorus oxychloride (10 mL) and stirred at 120° C. overnight. The cooled solution was poured into water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10–20% ethyl acetate/isohexane gave the product 2,6-dichloro-5-[(2-fluorophenyl)sulfonyl]pyridine (115 mg) and impure product (100 mg). The latter material was recrystallised from ethanol to give further clean product (42 mg, total yield 55%). δH (400 z, d6 DMSO): 8.68 (1H, dd, J=1.1, 8.3 Hz), 8.15 (1H, td, J=7.6, 1.7 Hz), 7.93 (1H, d, J=8.2 Hz), 7.89–7.85 (1H, m), 7.55 (1H, td, J=7.6, 0.9 Hz), 7.48–7.44 (1H, m); m/z (ES+) 306, 308 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[OH:22])[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:21]([O:22][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[C:12]([Cl:11])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)c(Cl)c1

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl 3-chloro-4-hydroxybenzoate (4 g, 21 mmol)(Lancaster) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl-phenoxy)-3-chloro-benzoic acid methyl ester as an off white solid (Yield 3.7 g, 50%).
Reaction SMILES: [Na].N.C([N:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:22][C:21]([CH3:24])([CH3:23])[CH:20]([OH:25])[CH:19]([NH:26][C:27]4C=CC(OCC)=C[CH:28]=4)[C:16]=3[CH:17]=2)[CH2:12][C:11]1=[O:36])C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[C:13]1([CH2:28][CH2:27][NH:26][CH:19]2[C:16]3[CH:17]=[C:18]4[C:13]([CH2:12][C:11](=[O:36])[NH:10]4)=[CH:14][C:15]=3[O:22][C:21]([CH3:24])([CH3:23])[CH:20]2[OH:25])[CH:14]=[CH:15][CH2:16][CH2:17][CH:18]=1
Reactant: CCOc1ccc(NC2c3cc4c(cc3OC(C)(C)C2O)CC(=O)N4Cc2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)Oc2cc3c(cc2C(NCCC2=CCCC=C2)C1O)NC(=O)C3
Yield: 19 %

Procedure:
Under nitrogen stream, sodium (90 mg, 3.91 mmol) was added to liquid ammonia (5 mL) at −78° C., and the resulting mixture was stirred. A solution of 1-benzyl-7-hydroxy-6,6-dimethyl-8-phenetylamino-3,6,7,8-tetrahydro-1H-pyrano[2,3-f]indole-2-one (173 mg, 0.39 mmol) in THF (2 mL) was added dropwise at −45° C., and the resulting mixture was stirred for 15 minutes. Upon the completion of the reaction, saturated ammonium chloride aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with water and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column (ethyl acetate) to obtain the aimed product (yield: 19%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:37]=[C:38]([C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[NH2:39]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15][N:37]=[C:38]([C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[NH2:39])=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: NC(=NO)c1ncccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=NOC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1)c1ncccn1
Reaction time: 2 h

Procedure:
To a suspension of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (200 mg, 0.64 mmol) in THF (2 mL) and DMF (2 mL) was added CDI (240 mg, 1.41 mmol) and stirred for 2 hours forming a clear solution. To this was added N′-hydroxypyrimidine-2-carboximidamide (115 mg, 0.84 mmol) and the resulting suspension stirred for 18 hours at room temperature. The solid was filtered off to yield crude N′-({2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}oxy)pyrimidine-2-carboximidamide, and suspended in THF (2 mL) and a solution of TBAF (1 M in THF, 0.64 mL, 0.64 mmol) was added and the mixture stirred for 15 minutes at room temperature. The volatiles were then removed in vacuo and the residue purified by Biotage flash chromatography, eluting with 2-6% MeOH/DCM to afford the title compound as a waxy white solid, 100 mg, 37%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.00 (d, 2 H), 8.56 (d, 2 H), 7.68-7.73 (m, 3 H), 7.27-7.33 (m, 2 H), 7.05 (t, 2 H), 6.77 (s, 1 H), 6.00 (s, 2 H), 4.18 (s, 2 H); m/z (APCI+) for C22H16N7FO 414.1 (M+H)+.