Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][CH2:45][C@@H:46]2[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[NH:40]>CN(C=O)C.CC(=O)OCC>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:40]=[C:39]([C:41]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:42]=3[CH2:43][CH2:44][CH2:45][C@@H:46]4[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (556 mg, 2.72 mmol) in DMF (10 mL) was added HOBt (476.6 mg, 3.53 mmol) and EDCI (677.9 mg, 3.53 mmol). After stirring for 30 min, (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (3.56 g crude, approximately 2.99 mmol) was added. After stirring at room temperature for an additional 90 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, and chromatographed (EA/hexanes) to provide 1.89 g (46%) (S)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-12 as a white solid. LCMS-ESI (m/z) calculated for C27H30N4O4: 474.6; no M/Z observed, tR=4.23 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.1 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.32 (dd, J=20.3, 12.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.94 (d, J=6.0 Hz, 1H), 4.88-4.72 (m, 1H), 3.23-3.08 (m, 1H), 3.07-2.94 (m, 1H), 2.06 (d, J=12.6 Hz, 1H), 1.97-1.78 (m, 3H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 172.64, 169.40, 162.69, 155.43, 138.65, 137.55, 134.04, 133.83, 131.68, 129.55, 126.08, 125.97, 116.74, 115.20, 113.53, 103.87, 79.44, 72.69, 48.97, 29.73, 28.40, 21.68, 19.71, 14.14.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]=2[C:34]=1[CH3:35])#[N:2].O.[OH-].[Li+].[O:39]1CCOCC1.O>CCOC(C)=O>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:8]2[C:7]3[C:34]([CH3:35])=[C:3]([C:1]([NH2:2])=[O:39])[CH:4]=[CH:5][C:6]=3[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: C1COCCO1
Reactant: Cc1c(C#N)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(N)=O)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-cyano-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (199 mg, 0.398 mmol) and lithium hydroxide monohydrate (50.1 mg, 2.295 mmol) in 1:1 dioxane-water was heated in a microwave reactor for 15 min at 100° C., followed by 30 min at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc, and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse-phase HPLC to provide the title compound. LC/MS: m/e 519.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.60 (1H, d), 7.35 (1H, d), 7.15 (2H, d), 7.03-7.10 (3H, m), 6.93 (1H, d), 5.19 (1H, d), 4.40 (1H, d), 2.60 (3H, s), 1.25 (9H, s).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C.O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 106.9 %

Procedure:
To a 20 mL vial containing a magnetic stir bar was added sodium hydride (103.7 mg, 4.32 mmol, 60% in mineral oil) followed by anhydrous DMF (2 mL) resulting in gas evolution. To this stirring reaction mixture was added 2-naphthol (623 mg, 4.32 mmol) as a solid in small portions over 5 min. The mixture was stirred at room temperature for 3 min and then 2,6-difluorobenzonitrile (601 mg, 4.32 mmol) in anhydrous DMF (4 mL) was added in one portion. The reaction mixture was heated in an oil bath at 100 ° C. for a total of 2 h and allowed to cool to room temperature. The reaction mixture was diluted with water (15 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (3×20 mL), dried (Na2SO4), filtered and concentrated to give K-1 as brown solid (1.216 g) of sufficient purity (contained 2-naphthol) to be used in the subsequent step. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)ncnc21
Reaction time: 2 h
Yield: 53.8 %

Procedure:
6-Chloropurine (5.0 g, 32 mmol) in DMF (75 mL) was treated with potassium carbonate (9.0 g, 65 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (7.0 g, 42 mmol) and stirred for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried (MgSO4), concentrated in vacuo and purified by column chromatography (SiO2, 20% EtOAc in isohexane) to give the title compound (4.9 g, 54%) as an off-white solid. δH (CDCl3) 8.82 (1H, s), 8.32 (1H, s), 5.71 (2H, s), 3.71-3.61 (2H, m), 1.03-0.93 (2H, m), 0.00 (9H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[CH2:14]([O:16][C:17](=[O:20])[CH2:18]Br)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:13])[C:3]=1[CH2:1][CH3:2])[CH3:15]
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C(C)=O)c(O)c1CC

Procedure:
1-(3-Ethyl-2,4-dihydroxy-phenyl)-ethanone was treated with 2-bromo-acetic acid ethyl ester and processed as described in the synthesis of example 20a. Yield, 96.89%; mp, 74-75° C.; MS (CI): 267 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].C(Cl)Cl.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](Cl)=[S:25])=[CH:19][CH:18]=1>O>[C:20]1([O:23][C:24](=[S:25])[O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([F:11])([F:12])[F:10])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: OC(c1ccccc1Br)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)C(OC(=S)Oc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
The title compound was prepared by an adaptation of the method described in Robins, M. J. et al. (J. Am. Chem. Soc. 1983, 105, 4059-4065). 1-(2-Bromo-phenyl)-2,2,2-trifluoro-ethanol (615 mg, 2.41 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar. DCM (4 mL) and TEA (1.2 eq., 0.403 mL, 2.89 mmol) were added via syringe. Phenyl chlorothionoformate (1.1 eq., 0.367 mL, 2.65 mmol) was added dropwise via syringe to the water-cooled solution. After completion of the addition, the reaction was stirred at RT for 16 h, poured into water, and extracted three times with DCM (10 mL). The combined organic extracts were dried over anhydrous MgSO4 filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 695 mg (74%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.58-7.68 (m, 2H), 7.36-7.48 (m, 3H), 7.27-7.36 (m, 2H), 7.04-7.15 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCc1cccc(Oc2ccnc(N)c2)c1
Solvent: c1ccncc1
Product: COC(=O)CCc1cccc(Oc2ccnc(NC(C)=O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 772.6 %

Procedure:
Methyl 3-{3-[(2-aminopyridin-4-yl)oxy]phenyl}propanoate (390 mg, 0.14 mmol) was dissolved in pyridine (5 mL) and the reaction mixture was cooled at 0° C. and stirred for 1 h. Acetic anhydride (135 μL, 0.14 mmol) was added dropwise and the reaction mixture was allowed to stir for 1 h. The reaction mixture was allowed to warm to rt and to stir overnight. The reaction was quenched with water and extracted with EtOAc. The organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified column chromatography to give the title compound (340 mg, 76%) as a white solid. LCMS: (FA) ES+ 315.29 (M+1).
Reaction SMILES: C([O-])(O)=O.[Na+].[SH:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[OH:14][CH2:13][C:9]1[CH:8]=[C:7]([S:6][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OCc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Yield: 58.5 %

Procedure:
Add NaHCO3 (12.0 g, 143 mmol) to a solution of (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) in DMF. Heat the mixture overnight. Dilute with ethyl acetate. Wash the mixture with water. Dry, filter and concentrate to afford the title compound (10.1 g, 59%) (Solidifies after standing). MS (APCI-pos) m/z (rel intensity): 243 (M+H, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[OH-].[Na+]>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a solution of 0.132 gm (0.57 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine in 5 mL of tetrahydrofuran were added 1.5 mL of triethylamine followed by 0.10 mL (0.13 gm, 0.85 mMol) of 4-fluorobenzoyl chloride. The resulting mixture was stirred at room temperature for 90 minutes at which time the reaction mixture was diluted with 0.1 N aqueous sodium hydroxide. This aqueous solution was extracted with dichloromethane and the organic phases were washed sequentially with water and saturated aqueous sodium chloride. The dichloromethane solution was dried over sodium sulfate and concentrated under reduced pressure. This residue was dissolved in dilute aqueous tartaric acid and then washed with dichloromethane. The aqueous phase made basic with aqueous sodium carbonate and was then extracted with dichloromethane. These dichloro-methane extracts were combined and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 5% methanol (containing 5% ammonium hydroxide) in chloro-form. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from toluene/hexane to provide 0.130 gm (64%) of the title compound in two crops.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)phenol (2.16 g, 10.6 mmol), disiobutylamine (0.14 mL) and sulfuryl chloride (0.59 mL, 7.4 mmol) in toluene was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature, treated with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was subjected to chromatography on silica gel, using hexane/ethyl acetate (20:1), to afford the title compound (1.7 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22]Br>C1COCC1.C(Cl)(Cl)(Cl)Cl>[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COc1cc(Br)c(CBr)c(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(Br)c(CCC(=O)OC(C)(C)C)c(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 5 mL of THF at −78° C. was added 6.5 mL of a 1.0M solution of lithium hexamethyldisilazane in THF. t-Butyl acetate (0.9 mL) was added dropwise to the resulting cold solution, and the resulting mixture was stirred for 10 min at −78° C. 2,6-Dibromo-4-methoxy-benzyl bromide (1.2 g) in 5 mL of CCl4 was added dropwise over 5 min. The mixture was stirred 20 min at −78° C., then quenched by addition of 1 mL of saturated aqueous NaHCO3. The mixture was warmed to room temperature, diluted with 50 mL of saturated aqueous NaHCO3, and extracted with 3×20 mL of EtOAc. The combined organics were washed with 25 mL of brine, dried over MgSO4, and concentrated to yield t-Butyl 3-(2,6-dibromo-4-methoxyphenyl)-propionate as an oily yellow solid. Mass spectrum (ESI) 320.9 (M-OtBu). 1H NMR (500 MHz, CDCl3): δ 7.08 (s, 2H); 3.76 (s, 3H); 3.20 (m, 2H); 2.45 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([OH:45])[CH:34]=2)=[N:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([O:45][C:14]3[CH:15]=[CH:16][C:11]4[C:10](=[O:20])[N:9]([CH3:21])[CH2:8][CH2:7][O:6][C:12]=4[C:13]=3[F:18])[CH:34]=2)=[N:27]1)[CH3:25]
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3F)OCCN(C)C4=O)cc(O[C@@H](C)COC)c2)n1
Temperature: 140 °C
Yield: 68.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (290 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 4 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified by column chromatography on alumina, eluting with 30-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (300 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](O)=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1OC

Procedure:
The product of Example 1B and 2-(3,4-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.92 (q, J=8.3 Hz, 1H), 3.80-3.83 (m, 5H), 3.78 (s, 3H), 3.75 (s, 3H), 3.59 (s, 2H), 3.17 (s, 1H), 3.08-3.10 (m, 3H); MS (ESI−) M/Z 423 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:22][S:23]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
Tert-butyl 3-hydroxypiperidine-1-carboxylate (3.6 g, 18 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C., triethylamine (4 mL) was added, followed by dropwise addition of methanesulfonyl chloride (2.28 g, 20 mmol) and DMAP (10 mg). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layer was washed with H2O, dried and concentrated to give crude product (5.5 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=2)[O:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][CH:30]=[C:19]([O:20][CH2:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]4[NH:43][N:42]=[N:41][N:27]=4)=[CH:24][CH:23]=3)[CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:34])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(OCc4ccc(-c5nnn[nH]5)cc4)c3)n(Cc3ccccc3)nc12

Procedure:
4-({3-[2-Benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}methyl)benzonitrile (37 mg, 1 eq) was treated with trimethylsilyl azide (21 μL, 2 eq) and di-n-butyltin oxide (5 mg, 0.3 eq) in toluene (2.5 mL) at 100° C. until full conversion. After cooling, most of the solvent was removed in vacuo and the residue was taken in methanol. Purification by flash chromatography, eluent 10% methanol in dichloromethane, afforded the title compound in 87% yleld.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]([O:15][CH2:16][CH2:17]O)[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.O>N1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]([O:15][CH2:16][CH2:17][Cl:3])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1
Reactant: N#CC(OCCO)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: N#CC(OCCCl)c1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.23 mL) was added dropwise to a solution of (3-bromophenyl)-(2-hydroxyethoxy)acetonitrile (3.62 g) in pyridine (12.1 mL) at 50° C., and the mixture was stirred at 60° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (elution solvent:heptane:ethyl acetate=9:1→8:2) to obtain 3.21 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([O:15]C(C2C=CC=CC=2)=O)=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([C:24]#[C:25][CH2:26][OH:27])[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[OH:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:24]#[C:25][CH2:26][OH:27])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(C#CCO)c2cccnc2c1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(C#CCO)c2cccnc2c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-hydroxy-prop-1-ynyl)-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (1.00 g, 2.76 mmol) in THF (14 mL) and water (14 mL) was added 1N NaOH (13.8 mL, 13.8 mmol) and the solution was stirred at 50° C. overnight. The THF was removed under reduced pressure and the remaining solution was acidified with 6N HCl to a pH=3. Injected the solution directly onto the Gilson auto-prep running a 95-50% H2O (0.1% TFA)/CH3CN (0.09% TFA) gradient over 35 minutes to obtain the desired compound as a bright yellow solid.