Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1B(O)O)=[O:6].[CH2:22]([C@@H:29]1[C@@H:38]([OH:39])[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[O:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[C:34]1[CH:33]=[C:32]2[C:37]([C@H:38]([OH:39])[C@@H:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][O:31]2)=[CH:36][CH:35]=1
Reactant: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A bi-phasic solution of 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (1.72 g, 5.66 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol(1.80 g, 5.63 mmol), sodium carbonate (1.82 g, 17.2 mmol), and tretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19 mol %) in toluene (15 mL) and water (9 mL) was stirred at reflux for 100 minutes. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with diisopropylether (75 mL). The organic extracts were washed with brine (50 mL), treated with Darco® G-60, dried over magnesium sulfate, filtered through Celite®, and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes 20/80) to provide (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield): Rf: 0.32 (ethyl acetate/hexanes25/75); IR 3407 (br), 2961, 1721, 1336, 1292, 1252, 1172, 1134, 1110, 1022, 848, 749 cm−1; 1H NMR (400 MHz, CDCl3) δ7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37 (m, 6H), 6.88-6.93 (m, 2H), 4.53 (t,J=4.4 Hz, 1H), 4.22 (dd, J=11.2, 2.5 Hz, 1H), 3.99 (dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H), 2.73 (dd, J=13.8, 6.3 Hz, 1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H), 1.81 (d, J=5.2 Hz, 1H), 0.74 (s, 9H); 13C NMR (100 MHz, CDCl3) δ26.64, 30.96, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97, 124.13, 126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25, 130.31, 139.08, 141.69, 142.03, 154.44, 168.14.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12](I)[NH:13][C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])=[CH:4][CH:3]=1>CO>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:12]3[NH:13][C:14]([CH2:15][CH2:16][CH3:17])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:19]=[CH:20][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[N:11]=3)[NH:13][C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCc1[nH]c(I)nc1C(=O)NCc1ccc(C)cc1
Solvent: CO
Product: CCCc1[nH]c(-c2nc(C(=O)NCc3ccc(C)cc3)c(CCC)[nH]2)nc1C(=O)NCc1ccc(C)cc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Iodide 6c (0.45 g; 1.2 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was triturated with CH3CN. The solid that remained undissolved was collected by filtration and washed with CH3CN to afford 0.30 g (38%) of 1c as an off-white microcrystalline solid. An analytical sample was recrystallized from CH3OH. mp 226–227 C; TLC (CH2Cl2-EtOAc, 1:1): Rf=0.60; 1H NMR (CD2Cl2): δ 0.80 (t, 6H), 1.59 (m, 4H), 2.21 (s, 6H), 2.86 (t, 4H), 4.39 (d, 4H), 7.05 (dd, 8H), 7.22 (br t, 2H); 13C NMR (DMSO-d6): δ 14.2, 21.4, 23.3, 27.0, 49.6, 128.3, 129.9, 131.0, 137.0, 138.7, 164.2; UV/vis (CH3OH): max (M−1cm−1)=287 (25100), 295 (25100), 310 (13700); LRMS (CI+): m/z (%): 513 (100) [M+H]+; HRMS (CI+): calcd for C30H37N6O2 513.2978; found 513.2981; Anal. calcd for C30H36N6O20.33(H2O): C, 68.68; H, 7.17; N, 16.02; found: C, 68.58; H, 7.17; N, 16,11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH2:31]=[O:32]>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[N:25]([CH2:31][OH:32])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)N1
Reactant: C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (500 mg, 1.17 mmol) in acetonitrile (15 mL) and pyridine (1.5 mL) was added formaldehyde (37% aq) (5.0 mL). The reaction mixture was stirred at 65° C. for 5 minutes. Cooled to room temperature and filtered off the resulting solid. Washed with water and dried under vacuum to provide 450 mg (84%) of (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 458 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)C.[OH-].[Li+]>CO>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCc1ccc2ncccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of 3-quinolin-6-yl-propionic acid ethyl ester (100 mg, 0.437 mmol) in methanol (2 mL) was added 4 M aqueous solution of lithium hydroxide (0.55 mL, 2.18 mmol). The reaction mixture was stirred at room temperature for 3 h then it was concentrated in vacuo, diluted with water, and treated with 1 N aqueous hydrochloric acid until pH 5. The aqueous layer was extracted with ethyl acetate (3×), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 18 mg of product as a white solid. 1H NMR 500 MHz (DMSO) δ 2.67 (t, 2H), 3.02 (t, 2H), 7.50 (dd, 1H), 7.67 (dd, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 8.29 (dd, 1H), 8.84 (dd, 1H); MS (m/z) 202 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](O)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH2:28]([NH2:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](=[O:20])(=[O:21])[NH:30][CH2:28][CH3:29])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(C)ccc1Cl
Reactant: CCN
Product: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OCC)cnc12
Yield: 87.4 %

Procedure:
Using 7-(2-chloro-5-methylphenylamino)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.72 g, 1.75 mmol) obtained in Example 12 step 2 and ethylamine (2.0 mol/L THF solution; 3.5 mL, 7.01 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.67 g, 87%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH3:13])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=1.[K].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@@:8]2([CH3:13])[NH:14][C:15](=[O:18])[CH2:16][O:12][C:9]2([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)(O)[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: CC1(C)OCC(=O)N[C@]1(C)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A dispersion of N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-2-chloro-acetamide (2.79 g, 7.91 mmol) in toluene (80 ml) at 23° C. was treated dropwise with a solution of potassium amylate (1.7 M in toluene, 24 ml, 41 mmol) within 30 minutes (slightly exothermic reaction). After complete addition the mixture was stirred at 23° C. for 45 minutes. For the workup, the reaction mixture was poured into hydrochloric acid (1M) and extracted with ethyl acetate. The organic layer was separated and washed with a saturated sodium hydrogen-carbonate solution and brine. The combined aqueous layers were re-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, then evaporated at reduced pressure to yield light brown oil. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate as the eluent. The (R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one was obtained as a light yellow gum (1.83 g, 73% of theory). Mass (calculated) C13H15BrFNO2 [316.168]; (found) [M+H]+=316, [M+2-H]+=318.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][C:10]=1[C:26]#[N:27])C1C=CC=CC=1>C1COCC1.C(O)C.[C].[Pd]>[C:26]([C:10]1[CH:11]=[C:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8])#[N:27]
Reactant: CCOC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Temperature: 25 °C

Procedure:
Ethyl 2-[4-(benzyloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylate was suspended in a mixture of THF and ethanol, then palladium-carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate. APN: 287.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:39]2[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:24]4[C:23]5[CH2:22][C:21]([CH3:20])([CH3:45])[CH2:30][CH2:29][C:28]=5[N:27]=[CH:26][N:25]=4)[CH2:37][C:36]=3[CH:38]=2)=[CH:4][N:3]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CN1CC[C@H](CNS(=O)(=O)c2cc(Br)cnc2N)C1
Product: CN1CC[C@H](CNS(=O)(=O)c2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2N)C1

Procedure:
Prepared according to the method of example 5 by using 2-amino-5-bromo-N-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.44 (br, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.05 (d, 1H), 4.70 (s, 2H), 4.31 (m, 2H), 3.97 (m, 2H), 3.16 (m, 1H), 3.04 (t, 2H), 2.94 (d, 2H), 2.67 (t, 2H), 2.67 (s, 3H), 2.47 (s, 2H), 2.52 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.65 (m, 3H), 0.92 (s, 6H); MS (EI) for C29H37N7O3S: 564 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.[CH2:25]([OH:28])[CH2:26][OH:27]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[CH:22]=[C:21]([O:27][CH2:26][CH2:25][OH:28])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Reactant: OCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(OCCO)ncn2)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To ethylene glycol (20 ml) is added sodium hydride (60% dispersion-type, 1.03 g), and thereto is added 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (1.66 g). The mixture is stirred at 60° C. for 20 hours. After cooling, the mixture is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from ethyl acetate to give 4-tertbutyl-N-{6-(2-hydroxyethoxy)pyrimidin-4-yl}benzenesulfonamide (1.58 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=NC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(Cl)Cl.[OH2:31]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: CC(C)(C)N=Cc1ccccc1CCCCCCCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine (0.51 g, 0.0146 mol) in tetrahydrofuran (5 mL) was added 10% aqueous hydrochloric acid (5 mL) and the mixture stirred for 15 h at room temperature. Methylene chloride (10 mL) and water (10 mL) were added and the layers separated. The aqueous layer was extracted with methylene chloride (1×15 mL) and the combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to an oil (0.405 g, 97.4% pure by HPLC assay, 92% corrected yield): IR (neat) 2920, 2880, 1695, 1600, 1455 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J=1.2 and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J=7.7 Hz), 2.58 (t, 2 H, J=7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][C:14]=3[CH3:21])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].P(Br)(Br)([Br:28])=O>C(Cl)Cl.CCOC(C)=O>[Br:28][CH2:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:22])[C:5](=[O:23])[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:12]3=[CH:11][CH:10]=2)[CH:18]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ccc(CO)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(CBr)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 51-1 (150 mg, 0.44 mmol) in DCM (2 mL) at 0° C. was added phosphorus oxybromide (126 mg, 0.46 mmol). After 4 hours, the reaction was diluted with EtOAc, and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give product as a white foam. MS (M+H)+: observed=402.0/404.0, calculated=402.3/404.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Cl:25])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:22]1[C:23]([Cl:25])=[C:24]2[C:19]([C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[F:27])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,545 mg) and sodium azide (230 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1,280 mg) as an amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].[Li]CCCC.[B:20](OC)(OC)[O:21]C.CC(=O)OCC>C1COCC1>[CH2:10]([C:9]1([CH2:12][CH3:13])[O:14][B:20]([OH:21])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2)[CH3:11]
Reactant: COB(OC)OC
Reactant: CCC(O)(CC)c1cc(C)ccc1Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CC)OB(O)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of 3-(2-bromo-5-methylphenyl)pentan-3-ol (6.5 g, 25.2 mmol) in THF (150 ml) at −78° C. was slowly added n-BuLi (30.24 ml, 75.6 mmol). The reaction mixture was warmed to rt and stirred for 2 h. After being cooled to −78° C., trimethyl borate (5.23 g, 50.4 mmol) was added dropwise and the reaction mixture was warmed to rt, stirred for 10 h under nitrogen and quenched with 2N HCl (50 ml). The mixture was extracted with EA (40 ml×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 1:1) to give the product (2.0 g, yield 38.9%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.87 (s, 1H), 7.52-7.47 (d, 1H), 7.11-7.06 (m, 2H), 2.35 (s, 3H), 1.88-1.68 (m, 4H), 0.60-0.45 (m, 6H). MS: m/z=205 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>C(Cl)Cl>[Br:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc(CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine (150.0 mg, 0.57 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (101.0 mg, 0.57 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 120.0 mg (76%), was isolated by column chromatography (2-5% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(Cl)Cl>O.C1COCC1>[C:23]([O:22][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1ccccc1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Temperature: 25 °C

Procedure:
A solution of the hydrobromide salt of 2-piperidin-4-yl-phenol Compound 3a (5.00 g, 19.37 mmol) in water (400 mL) was made basic to pH 8 by the addition of NaHCO3. A solution of O(Boc)2 (4.22 g, 19.36 mmol) in THF (80 mL) was added and the mixture was stirred at r.t. over night. CH2Cl2 (500 mL) was added and the organic layer was isolated and dried. The crude product was purified by chromatography to provide 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester Compound 2a (4.56 g, 85%) as a white powder 1H NMR δ 1.50 (s, 9H), 1.60 (m, 2H), 1.85 (bd, J=19.5 Hz, 2H), 2.82 (bm, 2H), 3.04 (m, 1H), 4.23 (bs, 2H), 6.7˜7.2 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[C:32]([O:39][CH2:40][CH3:41])=[CH:31][C:3]=1[CH2:4][N:5]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C-:42]#[N:43].[Na+].C(OCC)(=O)C.O>C(#N)CC.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]([C:2]1[CH:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[C:32]([O:39][CH2:40][CH3:41])=[CH:31][C:3]=1[CH2:4][N:5]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:43]
Reactant: [C-]#N
Reactant: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(Br)cc1C(=O)NC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(C#N)cc1C(=O)NC
Reaction time: 4 h
Yield: 31.8 %

Procedure:
After dissolving the tert-butyl N-{2-bromo-5-ethoxy-4-[(methylamino)carbonyl]benzyl}-N-{2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}carbamate (2.71 g) in propionitrile (11 ml), sodium cyanide (420 mg), copper iodide (163 mg) and tetrakis(triphenylphosphine)palladium (495 mg) were added under a nitrogen atmosphere and the mixture was heated to reflux for one hour. Additional copper iodide (170 mg) and tetrakis(triphenylphosphine)palladium (500 mg) were added and heating to reflux was continued for 4 hours. Ethyl acetate and water were added to the reaction mixture and the resultant mixture was filtered with celite. The filtrate was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and, after filtering off the insoluble portion, was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (788 mg) as a white solid.
Reaction SMILES: CN(C)C=O.[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[CH2:21][CH2:22][CH2:23][CH2:24]I.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:13][CH:6]([C:14]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(O)c2ccccc2)CCCC1
Temperature: 60 °C
Reaction time: 15.5 h
Yield: 76.4 %

Procedure:
To N,N-dimethylformamide (400 ml) were added ethyl benzoylacetate (25.1 g, 0.13 mol), 1,4-diiodobutane (40.47 g) (0.13 g) and anhydrous sodium carbonate (82.7 g, 0.78 mol) and the mixture was stirred at 60° C. for 15.5 h. The reaction mixture was poured into 1 L of water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dehydrated over anhydrous sodium sulfate and concentrated. A red residual solution (33.5 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to give the title compound (24.67 g) as a colorless oil (yield 77%).