Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:39]=4[C:40]([NH:42][CH3:43])=[O:41])[C:20]4[C:25]([CH3:26])=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:51][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[C:25]([CH3:26])[C:20]4=[C:19]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:39]=4[C:40]([NH:42][CH3:43])=[O:41])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1c(C)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)[nH]c2ncc(C)c1-2
Temperature: 120 °C
Yield: 67.5 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (249 mg, 0.348 mmol) was dissolved in dioxane (3 mL) and 2N NaOH (2 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 17 min. Reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (132 mg, 0.235 mmol) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.93 (m, 2 H) 2.11 (br. s., 6 H) 2.42 (s, 3H) 2.68 (br. s., 2 H) 2.81 (d, J=4.49 Hz, 3 H) 3.21 (s, 2 H) 3.66-3.74 (m, 2 H) 3.84 (s, 3 H) 6.70-6.78 (m, 1 H) 6.79-6.88 (m, 1 H) 6.88-6.98 (m, 1 H) 7.31-7.41 (m, 1H) 7.43 (s, 1 H) 8.34-8.42 (m, 2 H) 8.63-8.72 (m, 1 H) 9.49-9.59 (m, 1 H) 11.00-11.12 (m, 1 H). ESIMS (M+H)+=561
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[N+:13]([O-])=O.C(O)(=O)C>O.[Fe]>[Cl:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[N:5]=[CH:4][C:3]=1[NH2:13]
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cnn(C2CCOCC2)c1Cl
Temperature: 90 °C
Yield: 52 %

Procedure:
To a suspension of 5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (1 equiv) and iron dust (3 equiv) in water (0.35 M) was added acetic acid (3.54 M). The mixture was heated to 90° C. for 1.5 h then cooled to room temperature. The reaction was quenched by addition of solid sodium bicarbonate and treated with ethyl acetate (0.06M) with continuous stirring. The mixture was filtered and the filter cake was rinsed with ethyl acetate. The combined filtrate was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (52% yield) as a brown oil. MS (ESI) m/z 202.1 [M+H]+.
Reaction SMILES: [Na+].[CH3:2][Si:3]([CH3:17])([CH3:16])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O-:15])=O)[N:10]=[CH:9]1.[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.CN(C=O)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:2])([CH3:17])[CH3:16])[CH:12]=2)=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C(=O)Nc2ccccc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A flask was charged with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylate sodium salt (70 mg, 0.26 mmol) (as prepared in the previous step), 2-piperidin-1-yl-phenylamine (36 mg, 0.20 mmol), EDCI (60 g, 0.31 mmol), DMAP (25 mg, 0.20 mmol), and DMF (1 mL) and stirred for 3 h at RT. The reaction was diluted with EtOAc (10 mL) and washed with brine (2×10 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 5-g SPE cartridge (silica) with 30% EtOAc/hexane to give 80 mg (97%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H32N4O2Si, 401.2 (M+H), found 401.1.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3/[CH:11]=[N:12]/C(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)=[N:7][O:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].I[CH2:41][CH:42]1[CH2:44][CH2:43]1.Cl>O1CCCC1.CC(C)=O>[Br:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3[CH:11]([NH2:12])[CH2:41][CH:42]3[CH2:44][CH2:43]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ICC1CC1
Reactant: Fc1ccc(C(/N=C/c2ccccc2-c2noc3cc(Br)ccc23)c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: NC(CC1CC1)c1ccccc1-c1noc2cc(Br)ccc12
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of (E)-N-(2-(6-bromobenzo[d]isoxazol-3-yl)benzylidene)-1,1-bis(4-fluorophenyl)methanamine (Compound 8) (1.34 g) in dry tetrahydrofuran (15 mL) under nitrogen was cooled to −78° C. with stirring and a 1M solution of potassium tert-butoxide in tetrahydrofuran (3.2 mL) added dropwise. Solution turned dark purple. After 20 min (iodomethyl)cyclopropane (1.45 g) was added in one portion and solution slowly warmed to room temperature, stirred at this temperature for 1.5 h then quenched by the addition of water (10 mL) and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated to leave a dark red gum that was dissolved in acetone (20 mL) and an aqueous 2N HCl solution (15 mL) added and the mixture stirred overnight. The acetone was removed by evaporation and the aqueous solution extracted with dichloromethane. The aqueous solution was made basic with sodium bicarbonate and extracted with dichloromethane, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. SCX purification (eluting with methanol then ammonia in methanol) followed by flash chromatography on silica eluting with 0 to 5% methanol in dichloromethane gave the title product (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1COCC1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[CH:21][CH:20]=1>[Cu](I)I.C(N(CC)CC)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc2nc(Nc3ccc(Cl)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a mixture of methyl 3-amino-2-hydroxybenzoate (700 mg) and THF (21 mL) was added 4-chlorophenylisothiocyanate (717 mg), followed by stirring at room temperature overnight. To the reaction mixture were sequentially added copper iodide (0.87 g) and triethylamine (641 μL), followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and methanol was added thereto, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and then triturated with n-hexane-ethyl acetate (10:1, 11 mL) to obtain methyl 2-[(4-chlorophenyl)amino]-1,3-benzoxazole-7-carboxylate (270 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[N:24][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[N:24][CH:25]=2)=[C:3]([CH2:10][OH:11])[CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OCc1cc(F)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CO)cn1

Procedure:
(2-bromo-4,5-difluorophenyl)methanol (2.8 g, 12.5 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (4.8 g, 13.7 mmol), Pd(dppf)Cl2 (1.4 g, 1.9 mmol), and K2CO3 (3.4 g, 24.9 mmol) were dissolved in 1,4-dioxane (28 mL) and water (15 mL) and the resulting mixture was heated to 85° C. After 2 h the resulting mixture was diluted with EtOAc and the layers were separated. The organic layer was dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compond was prepared from 3-pyridin-2-yl-benzoic acid methyl ester [CAS-No. 98061-20-2] (9.42 g, 44.18 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (8.35 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccncc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(c1ccncc1)N1CCNCC1

Procedure:
The title material was synthesized from the title product of Example 26 (1.3 g, 4.46 mmol) by the method described in Example 25, except that the title free base was generated by treatment of its HCl salt with 0.5N K2CO3 in CH2Cl2. The CH2Cl2 solution was dried over Na2SO4 and all solvent removed under reduced pressure to provide 333 mg of the title free base. This material was used without further purification.
Reaction SMILES: N[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.N([O-])=O.[Na+].[I-:14].[K+].CCOC(C)=O>O1CCCC1.Cl.O>[I:14][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9]
Reactant: [I-]
Reactant: Cc1cc(O)ccc1N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1I
Reaction time: 0.42 h

Procedure:
To a solution of 4-amino-meta-cresol (20.59 g, 167 mmol) in 90 mL of tetrahydrofuran and 280 mL of 3M HCl solution at 0° C. was added a solution of NaNO2 (12.73 g, 184 mmol) in 40 mL of water dropwise over 5 minutes. After 25 minutes, a solution of potassium iodide (112.5 g, 678 mmol) in 85 mL of water was added, and stirring was continued for 15 minutes. The solution was poured into EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (0-50% EtOAc/hexane) to provide the desired product as a dark crystalline solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: ClCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1

Procedure:
264.0 g. of (R)-2-hydoxy-isocaproic acid were dissolved in 1.8 liters of absolute dioxan in a three-necked flask fitted with a stirrer, thermometer and reflux condenser with a calcium chloride tube. The solution was treated successively with 285 ml. of triethylamine and 236 ml. of benzyl chloride and heated at an internal temperature of 100° for 20 hours with stirring in an oil-bath. After cooling, the resulting triethylamine hydrochloride was filtered off and washed with 500 ml. of ethyl acetate. The filtrate was evaporated under reduced pressure at 50°. The residual oil was dissolved in 800 ml. of ethyl acetate and washed twice with 150 ml. portions of 3-N hydrochloric acid, twice with 100 ml. portions of 5 percent sodium chloride solution, twice with 150 ml. portions of 10 percent potassium bicarbonate solution and twice with 100 ml. portions of 5 percent sodium chloride solution. After each of these washings, the oil was rinsed with 200 ml. of ethyl acetate. The ethyl acetate solutions were dried over magnesium sulphate and evaporated under reduced pressure at 50°. The crude product which was thus-obtained was distilled at 0.3 Torr (112°-115°). There was obtained benzyl-(R)-2-hydroxy-isocaproate; [α]D25 = + 18.0° (c = 1 in methanol); nD23 = 1.498.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCC(CO)CC2)nn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(COc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 6-(4-hydroxymethylpiperidin-1-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.275 g, 0.90 mmol) in THF (10 mL) was added 2-hydroxybenzotrifluoride (0.178 g, 1.10 mmol), triphenylphosphine (0.289 g, 1.100 mmol) and diethyl azocarboxylate (0.5 mL, 1.10 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the obtained crude product was purified by column chromatography to yield the title compound in 40% yield (0.035 g). 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=9.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.47-7.42 (m, 1H), 6.99-6.92 (m, 3H), 4.57-4.53 (m, 2H), 3.89 (d, J=5.9 Hz, 2H), 3.56-3.49 (m, 2H), 3.11-3.02 (m, 2H), 2.25-2.15 (m, 1H), 2.01-1.97 (m, 2H), 1.52-1.41 (m, 2H), 1.27-1.20 (m, 2H), 0.75-0.68 (m, 1H), 0.47-0.41 (m, 2H), 0.09-0.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.3, 160.0, 156.7, 144.3, 133.3, 127.2, 127.1, 126.8, 125.5, 120.1, 112.5, 112.2, 72.6, 44.9, 39.6, 36.1, 34.6, 28.2, 8.7, 4.2. MS (ES+) m/z 449 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[CH:55](/B(O)O)=[CH:56]\[CH3:57]>>[CH2:33]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[C:30]([C:25]1[C:26]([Cl:29])=[C:27]([CH3:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[NH:14][S:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH2:53][CH3:54])=[CH:3][C:2]=3/[CH:55]=[CH:56]/[CH3:57])(=[O:13])=[O:12])=[CH:18][C:19]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:24]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3Br)CCN4CC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: C/C=C/B(O)O
Product: C/C=C/c1cc2c(cc1S(=O)(=O)NC(=O)c1ccc(-n3nc(C(=O)N(CCCC)CCCC)c(Cl)c3C)c(C(=O)N3CCc4ccccc4C3)c1)N(CC)CC2
Yield: 23.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 87, 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 35 mg, 0.042 mmol) and (E)-prop-1-enylboronic acid (14 mg, 0.17 mmol) were converted to the title compound (8 mg, 22%) as a white solid. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.03-7.99 (m, 1H), 7.88-7.87 (m, 1H), 7.72-7.67 (m, 1H), 7.31-7.12 (m, 6.5H), 6.94-6.93 (m, 0.5H), 6.05-5.90 (m, 1H), 4.75-4.40 (m, 2H), 3.95-3.55 (m, 1H), 3.47 (t, J=8.4 Hz, 2H), 3.27-3.15 (m, 2H), 3.26 (q, J=7.0 Hz, 2H), 3.01 (t, J=7.9 Hz, 2H), 2.80-2.60 (m, 2H), 2.34 (s, 2H), 2.30 (s, 1H), 2.09-2.07 (m, 1H), 1.85-1.83 (m, 2H), 1.55-0.90 (m, 14H), 0.95-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.70 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 799.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O.[Br:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)=[CH:9][C:10]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1O
Reactant: BrCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenol (0.24 g, 0.97 mmol) (Example 33) in DMF (2 mL, containing 1% v/v of water) was added 1,2-dibromoethane (1.09 g, 5.82 mmol), and the mixture was stirred at rt for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was suspended in EtOAc, filtered through a small plug of silica, and the filtrate was concentrated. The crude material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.79-7.68 (m, 2H), 6.88-6.78 (m, 2H), 4.34 (t, 2H), 3.69 (t, 2H), 2.95-2.82 (m, 2H), 2.72-2.60 (m, 2H), 1.80-1.64 (m, 2H), 1.36 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C@H:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1.[OH-].[Na+:28]>C(O)C>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O-:21])=[O:20])[C@H:11]([C:15]([F:17])([F:18])[F:16])[O:12]2)=[CH:7][CH:6]=1.[Na+:28]
Reactant: Cc1ccc(C)c(Oc2ccc3c(c2)O[C@@H](C(F)(F)F)C(C(=O)O)=C3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)c(Oc2ccc3c(c2)O[C@@H](C(F)(F)F)C(C(=O)[O-])=C3)c1
Yield: 97 %

Procedure:
A solution of 53.8 mg (0.148 mmole) of (2R)-(−)-7-(2,5-dimethylphenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 1.5 mL of ethanol was treated with 1.47 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 55.6 mg (97%) of an off-white solid: MS (ES+) 365 (M+1, 100); 1H NMR (CD3OD/400 MHz) 2.09 (s, 3H), 2.28 (s, 3H), 5.77 (q, 1H, J=7.3 Hz), 6.31 (d, 1H, J=2.4 Hz), 6.41 (dd, 1H, J=8.3 Hz, J=2.3 Hz), 6.78 (s, 1H), 6.94 (d, 1H, J=7.7 Hz), 7.14 (m, 2H), 7.38 (s, 1H); 19F NMR (CD3OD/400 MHz) 80.2 (d, 3F, J=7.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][CH2:13][C:14]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:8][CH3:9])=[O:15]
Reactant: O=C(Cl)CCCCl
Reactant: CSc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1cc(F)ccc1C(=O)CCCCl
Temperature: 20 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of 1-fluoro-3-(methylsulfanyl)benzene (1.98 g, 14.0 mmol) and 4-chlorobutyryl chloride in CH2Cl2 (15 mL) was added AlCl3 (2.06 g, 15.4 mmol) at 20° C. under N2. The reaction mixture was stirred for 15 h at 20° C. for 12 h then quenched by addition of H2O and extracted with Et2O. The combine organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was recrystalized to give 4-chloro-1-[4-fluoro-2-(methylsulfanyl)phenyl]-1-butanone (2.80 g, 81%) as a white needle shape crystal.
Reaction SMILES: C(O)CCC.C(O)CCCCCCC.S(=O)(=O)(O)O.[OH:20][C@H:21]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23]>O>[O:20]=[CH:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: CCCCCCCCO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A maleic acid ester of an APG was prepared as follows. To a 1 L erlenmeyer flask, containing a magnetic stir bar, was added 185.1 g anhydrous n-butanol (Aldrich, 99.8%), 36.1 g n-octanol (Aldrich, 99+%), and 2.0 g deionized water. To the stirred mixture, 0.184 g (100 mL) of concentrated sulfuric acid (J. T. Baker, 96.6%) was added using a 1 mL glass syringe. This mixture was added to a 500 mL three necked round bottom flask containing 50.0 g of anhydrous α-D-glucose (Aldrich, 96%) and a concave magnetic stir bar. The flask was fitted with a thermocouple probe, a dry air intake, and a 25 mL Barrett receiver on which two glass condensers were mounted, which were connected to a gas bubbler. The condensate collection side of the Barrett receiver was filled with n-heptane, and the gas flow-through side was wrapped in cotton wool for the purpose of insulation. Dry air, passed over a 10 inch column filled with dry molecular sieves and Drierite, was passed through the liquid phase in the round bottom flask. The flask was heated for 4 hours at about 95° to 100° C. using a temperature controlled oil bath. Approximately 12 mL of condensate water was collected in the Barrett receiver as a result of glucose oligomerization reaction and the aldol condensation reaction to give alkylation at the C1 position. The white suspension of sugar particles disappeared as the reaction from glucose to APG proceeded until a clear solution was obtained. This demonstrated that the APG is soluble in the alcohol. The resulting APG solution was colorless, indicating that byproduct formation of colored bodies, such as furfurals, was minimized.
Reaction SMILES: [CH3:1][C:2]([NH2:10])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(#N)C>[CH3:1][C:2]([NH:10][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CNC(C)(C)c1ccccc1
Reaction time: 24 h
Yield: 58.4 %

Procedure:
13.5 g (0.1 mol) of α,α-dimethylbenzylamine was dissolved in 200 ml of acetonitrile, and 15 g (0.11 mol) of potassium carbonate was added thereto. 15.3 g (0.1 mol) of methyl bromoacetate was gradually dropwise added thereto under cooling with ice. After completion of the dropwise addition, reaction mixture was returned to room temperature and stirred for one day and night. Salts were removed by filtration, and acetonitrile was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation to obtain 12.1 g (yield: 60%) of the desired compound.