Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=3)[CH:19]=[CH:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Yield: 87.1 %

Procedure:
90.0 g of methyl 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylate was dissolved in a mixed solution consisting of 760 ml of methanol and 200 ml of tetrahydrofuran. Thereafter, 92 ml of a 5 N sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was then heated to a temperature between 60° C. and 70° C. After completion of the reaction, the reaction solution was cooled, and 65.0 g of ammonium chloride was added thereto, followed by concentration under a reduced pressure. A 5% KHSO4 aqueous solution was added to the residue, so as to adjust pH to be 5 to 6, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. Thereafter, the residue was solidified, and then collected from a mixed solvent consisting of hexane and t-butylmethyl ether by filtration, so as to obtain 75.6 g of the subject compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]=[C:25]=[O:26])=[O:23])[N:15]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([NH:24][C:25]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:26])=[O:23])[N:15]=1
Reactant: C1COCCN1
Reactant: O=C=NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCOCC1)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Yield: 96.6 %

Procedure:
Morpholine (114 μL; 1.30 mmol, 2.0 eq.) is added to a solution of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl isocyanate (Compound A4, 200 mg, 0.65 mmol) in anhydrous dichloromethane (4.0 mL) under nitrogen, and the reaction mixture is heated to reflux for 18 h. The resulting slurry is filtered and recrystallized from the minimum amount of dichloromethane in hexanes to afford 249 mg (97%) of morpholine-4-carboxylic acid 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoylamide (Compound 25) as a white powder: mp 190-194° C.; 1H NMR (300 MHz, DMSO-d5) δ 3.05 (t, 5.1 Hz, 2H), 3.46 (d, 4.5 Hz, 2H), 3.61 (m, 2H), 3.76 (t, J=5.1 Hz, 2H), 7.46-7.90 (m, 4H), 7.59 (d, J=8.1 Hz, 1H), 8.22-8.29 (m, 2H), 8.53 (d, J=1.5 Hz, 1H), 9.20 (br s, 1H); MS m/z 397.15, calcd for C20H17FN4O4 (MH+) 397.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=1)[CH2:13][CH3:14])=[O:11].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:30])([CH3:31])[C:23]([OH:25])=[O:24])=[CH:32][CH:33]=1)[CH2:13][CH3:14])=[O:11]
Reactant: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)Nc1ccc(C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(NCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(C)cc1C
Yield: 75.8 %

Procedure:
Similarly to the procedure of Example 1-9, 170 mg (0.374 mmol) of tert-butyl 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate (Example 1-7) are reacted with 0.72 ml (9.35 mmol) of trifluoroacetic acid in 3 ml of dichloromethane to give 113 mg (72%) of 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionic acid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[K+].Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1CCl.[C:37]([OH:44])(=[O:43])[CH2:38][CH2:39][C:40]([OH:42])=[O:41]>CO.C(O)(C)C.C1(C)C=CC=CC=1>[C:37]([OH:44])(=[O:43])[CH2:38][CH2:39][C:40]([OH:42])=[O:41].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C(O)CCC(=O)O
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1SCc1ccccn1)CCNCC2
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 equiv.) in methanol (0.1-0.4 M) and add potassium hydroxide (8-20 equiv.). Stir at 60° C. for 4-24 h. Cool the reaction mixture in an ice bath, add picolyl chloride hydrochloride (1-3 equiv.) and stir the mixture at ambient temperature for 16-24 h. Add a volume of toluene approximately equal to the volume of the reaction mixture and concentrate the resulting mixture to approximately ½ the resulting total volume and repeat this process once more. Add water until all solids dissolve and separate the layers. Dry the organic layer over Na2SO4 and filter. Heat the solution (containing about 0.25-0.40 M of free base of the title compound) to 50-75° C. and then optionally seed with previously formed crystals of the title compound. Add succinic acid (1-1.3 equivalents) in isopropyl alcohol (0.25-0.40M solution) to the solution over 545 min. Cool the solution to 20-25° C. over 1-3 h and filter, rinsing with a solution of toluene/isopropyl alcohol (1:1). Dry the resulting solid under vacuum at 50-70° C./5 Torr to give the title compound as a white solid, mp 159-160° C. Anal. Calc'd for C20H23ClN2O4S: C, 56.80; H, 5.48; N, 6.62. Found: C, 56.56; H, 5.41; N, 6.57.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][NH:22][CH2:21][CH2:20]2>C(O)(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:21][CH2:20]2
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)COc1ccc([N+](=O)[O-])cc1)CC2
Yield: 95.5 %

Procedure:
A mixture of 1,2-epoxy-3-(4-nitrophenoxy)propane (4 g) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5.4 g) in isopropanol (100 ml) was heated under reflux for 3 h and evaporated. The residue was purified by column chromatography to give the title compound (7.6 g) as a yellow oil which solidified on standing.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(COS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a mixture of 8-(4-hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 86) in pyridine at 0° is added methanesulfonyl chloride (1.2 equivalents) in pyridine. The mixture is stirred at 0° until complete conversion is achieved and then the solvent removed under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:39][CH2:40][CH2:41][CH2:42][S:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:13]=1[OH:14])[C:8]([NH:39][CH2:40][CH2:41][CH2:42][S:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCSc1ccncc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCCCSc2ccncc2)cc(C(C)(C)C)c1O
Yield: 27.3 %

Procedure:
To a solution of 1.49 g (5.94 mmol) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 889 mg (7.73 mmol) of N-hydroxysuccinimide in 60 ml of methylene chloride was added 1.38 g (7.13 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. Further 1.00 g (5.94 mmol) of 4-(3-aminopropylthio)pyridine was added and the mixture was stirred at rcom temperature for 8 hours. The reaction mixture was washed with water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 650 mg of the desired compound (27.3%, colorless powder), mp: 203.0°-204.0° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]>C(OCC)(=O)C.C(O)C>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)NCCC(=O)OC)cc1N

Procedure:
The same procedure is used as in (2). Rf value: 0.28 (silica gel; ethyl acetate/ethanol=50:2)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Temperature: 4 °C
Yield: 91.8 %

Procedure:
A mixture of 2,4,5-trifluoronitrobenzene (5.4 g, 30.8 mmol), benzylalcohol (3.2 mL, 30.8 mmol) and potassium carbonate (6.4 g, 46.1 mmol), in DMF (20 mL), was stirred at ambient temperature for 72 h. Water (60 mL) was added and the mixture was cooled at 4° C. for 24 h. The resultant precipitate was filtered, rinsed with water and dried in vacuo to afford the product (7.5 g, 92%) as a pale yellow solid. 1H NMR (CDCl3) δ 7.90-7.94 (m, 1H), 7.38-7.44 (m, 5H), 6.85-6.90 (m, 1H), 5.22 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7-Bromo-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (117 g) was dissolved in hot toluene (2 L) and poured into stainless steel Parr vessel. Additional toluene (2 L) and 5% platinum on carbon (12.5 g) were added. The vessel was evacuated, charged with hydrogen (54 psi, 3.7×105 Pa), and shaken overnight at room temperature. The reaction mixture evacuated, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44]([CH:47]=1)[CH:45]=O>CN(C)C=O>[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](/[CH:45]=[CH:6]/[C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:47]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCOP(=O)(Cc1cccc(OC)c1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-methoxybenzylphosphonate (5 g, 19.36 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.092 g, 38.7 mmol) and 18-Crown-6 (2.047 g, 7.74 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 5-bromonicotinaldehyde (4.32 g, 23.23 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 2 h. The reaction was poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to an oil which crystallized upon standing. The solid was triturated with a minimum of ethanol (ca. 12 mL) and placed in the freezer for 72 h. The resulting solid was broken up with a spatula, collected by filtration, and rinsed with a minimum of cold ethanol to give 3.79 g (68%) as a white crystalline solid. 1H-NMR (CDCl3, 500 MHz) δ 8.64 (d, J=1.8, 1H), 8.57 (d, J=2.1, 1H), 8.00 (dd, J=2.1, 1.8, 1H), 7.33 (dd, J=7.9, 7.9, 1H), 7.10-7.20 (m, 2H), 7.07 (m, 1H), 7.01 (d, J=16.5, 1H), 6.91 (dd, J=7.6, 2.1, 1H), 3.88 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.1, 149.5, 146.7, 137.7, 135.1, 134.8, 132.4, 130.0, 123.7, 121.1, 119.6, 114.4, 112.2, 55.4. Mass spec.: 290.14 (MH)+.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:43])([CH:33]([O:37]C(=O)C(C)=C)[CH:34](C)C)[C:15]([O:17][CH2:18]CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=[O:16].C(=O)([O-])O.[Na+]>CO>[F:43][C:14]([F:13])([C:33]([OH:37])([CH3:34])[CH3:2])[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(C)C(=O)OC(C(C)C)C(F)(F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1>>[CH3:19][C:5]1[N:4]([CH2:3][CH:2]([O:1][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH3:20])[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: Oc1cccnc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1cccnc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 3-pyridinol; MS (ES) m/z 360 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9]Br>CN(C=O)C>[OH:8][C:3]1[C:2]([F:1])=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1
Reactant: Oc1ncccc1F
Reactant: BrBr
Solvent: CN(C)C=O
Product: Oc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 3-fluoro-2-hydroxypyridine (1 g, 8.8 mmol) in dry DMF (11 mL) was cooled in an ice bath. Bromine (1.55 g, 9.7 mmol) was added dropwise over a period of 10 min and the reaction mixture stirred at 0° C. for 1 h then allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched with water. The aqueous was extracted with DCM (×4) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20-100% EtOAc in petroleum ether 40-60) yielded the target compound as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:6][C:7]1[CH:14]=[C:13]([O:15][CH2:2][CH2:3][CH2:4][Cl:5])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCCCl)cc1Cl
Temperature: 65 °C
Yield: 84.5 %

Procedure:
1-Bromo-3-chloropropane (2.55 g, 16.2 mmol, 1.0 equiv) was added to a solution of 2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2 mmol) and K2CO3 (4.48 g, 32.4 mmol) in acetonitrile (41 mL). The mixture was heated at 65° C. for 18 h, then cooled to room temperature (rt) and filtered through diatomaceous earth. The filtrate was concentrated to yield the crude product, which was purified by column chromatography (silica gel, 5% EtOAc in hexanes) to afford 3.19 g of a colorless oil (66%). 1H NMR (400 MHz, CD3OD): 10.3 (s, 1H), 7.87 (d, J=8.0, 1H), 7.10 (d, J=4.0, 1H), 7.03 (dd, J=8.0, 4.0, 1H), 4.23 (t, J=8.0, 2H), 3.76 (t, J=8.0, 2H), 2.31-2.22 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:12]([N+:24]([O-:26])=[O:25])[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[N+:24]([C:12]1[CH:11]=[C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])([O-:26])=[O:25]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A suspension of 2-thiophene boronic acid (3.93 g, 30.7 mmol), bromoarene 2 (7.31 g, 23.1 mmol), tri-o-tolyl-phosphine (2.16 g, 7.1 mmol) and potassium carbonate (9.81 g, 70.9 mmol) in degassed ethyleneglycol dimethylether (DME) (120 mL) and H2O (40 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (1.78 g, 1.5 mmol). The mixture was stirred in a preheated oil bath at 80° C. for 18 h, diluted with AcOEt (200 mL), washed with brine, dried over MgSO4 and concentrated. The crude material was either purified by flash chromatography (eluent: 10% AcOEt in hexane) or triturated in a mixture AcOEt:hexane (10:1, 100 mL) to give title compound 3 (6.74 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[C:26]([C:28]1[CH:29]=[C:30]([O:34][C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42](OC)=[O:43])[CH:36]=2)[CH:31]=[N:32][CH:33]=1)#[N:27].Cl>C1COCC1.CCOC(C)=O>[C:26]([C:28]1[CH:29]=[C:30]([O:34][C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=3)=[O:43])[CH:36]=2)[CH:31]=[N:32][CH:33]=1)#[N:27]
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)c1cc(Oc2cncc(C#N)c2)cc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cncc(C#N)c2)cc(C(=O)Nc2ccc(F)cn2)n1
Reaction time: 0.08 h
Yield: 46 %

Procedure:
2-Amino-5-fluoropyridine (34.3 mg, 0.306 mmol, 1.10 eq) was dissolved in THF (0.7 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (0.613 mL, 0.306 mmol, 1.10 eq) was added dropwise and the reaction was stirred for 5 minutes. Methyl 4-(5-cyanopyridin-3-yloxy)-6-methylpicolinate (75 mg, 0.28 mmol, 1.0 eq) was added as a solution in THF (0.7 mL) and the reaction was stirred for 30 minutes. The reaction was diluted with EtOAc, neutralized with 1N HCl, and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 45 mg (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.99 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.41-8.39 (m, 2H), 8.27 (dd, J=9.1, 4.1 Hz, 1H), 7.86 (td, J=8.7, 2.8 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 2.58 (s, 3H); [M+1]+: 350.2.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:29]O>>[CH3:29][O:10][C:9](=[O:11])[C:8](=[N:12][NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Temperature: 25 °C

Procedure:
To a suspension of 4b (0.1 mmol, 34 mg) in MeOH (2 mL), was added dropwise thionylchloride (22 μL, 0.3 mmol) at −30° C. Then, the solution was allowed to warm at room temperature. The reaction mixture was heated to reflux and concentrated to afford the desired product. The crude is purified by silica gel chromatography (EtOAc/MeOH 10/1) to give the pure compound as a yellow solid (11 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][Si:12](Br)([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][Si:12]([CH3:14])([CH3:13])[NH:4][C:3]1[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[Cl:1]
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: C[Si](C)(C)Br
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(Cl)c(N[Si](C)(C)C)c1Cl
Yield: 73.6 %

Procedure:
A solution of 50 ml of benzene, 4.0 g (22.7 mmole) of 2,6-dichloro-3-methylaniline, 10.67 ml (80.8 mmole) of trimethylsilyl bromide, and 13.1 ml (94.0 mmole) of triethylamine was heated at reflux over 42 hours. The product was isolated as described in Example 1 to provide 4.14 g (16.7 mmole, 73.5 percent yield) of 98.0 percent pure N-trimethylsilyl-2,6-dichloro-3-methylaniline as a light yellow oil, b.p. 64°-68° C. at 0.03 mm.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:5][CH2:4][CH2:3][OH:6]
Reactant: OCCO
Reactant: BrCc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 1.23 g) was added portionwise to a solution of ethane-1,2-diol (4.7 mL) in THF (70 mL) and the mixture was stirred at RT for 30 min. 1-Bromo-3-(bromomethyl)benzene (7 g) was added, followed by tetrabutylammonium iodide (1.03 g) and the reaction mixture was heated at reflux for 90 min. The mixture was diluted with water and extracted into ethyl acetate (×2). The combined organics were dried over MgSO4, filtered and evaporated. The crude product was purified by silica chromatography using 30% ethyl acetate in isohexane as solvent to afford the subtitled compound as a colourless oil. Yield 4.90 g.