Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[C:18]([S:22]([NH2:24])=[O:23])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CO.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[C:5](/[C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:24]\[S:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1ncccc1C(=O)c1cccc(Br)c1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Titanium(IV)ethoxide (1 M solution in THF, 18.7 mL) was added to a solution of 3-(3-bromobenzoyl)pyridine-2-carbonitrile (2.680 g, 9.334 mmol) and tert-butylsulfinamide (1.244 g, 10.27 mmol) in anhydrous THF (10 mL) under an atmosphere of argon. The mixture was heated at 50° C. for 70 h. After cooling to room temperature the mixture was diluted with methanol (20 mL) and 100 drops of water was added. The resulting mixture was allowed to stand for about 1 h and then filtered through a pad of sodium sulfate. The filter cake was taken up in saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The mixture was stirred over night, the phases were separated and the aqueous phase was extracted with dichloromethane. The extracts were combined with the filtrate from above, dried over sodium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of acetonitrile in dichloromethane (0-20%) gave 2.52 g (69% yield) of the title compound. 1H NMR (CDCl3) δ 8.81 (d, 1H), 7.76 (m, 2H), 7.68 (m, 1H), 7.62 (dd, 1H), 7.43 (d, 1H), 7.32 (t, 1H), 1.39 (br. s., 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:5][CH3:6]
Reactant: CC[C@H](COC)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](COC)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.7 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methoxymethyl-propyl)-amide (40 mg, 0.074 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (500 μl, 7.4 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (11:1:1 hot heptane/dichloromethane/EtOAc) to afford 21 mg (69%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methoxymethyl-propyl)-amide as an off-white solid. MS: [M+H]+=413; 1H NMR (DMSO-d6) δ: 12.84 (br. s., 1H), 9.12 (s, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.45 (s, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.7, 1.5 Hz, 1H), 4.16-4.27 (m, 1H), 4.18 (s, 3H), 3.57 (dd, J=9.6, 4.3 Hz, 1H), 3.47 (dd, J=9.6, 4.3 Hz, 1H), 3.27 (s, 3H), 1.71-1.89 (m, 1H), 1.47-1.71 (m, 1H), 0.96 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH:40]=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5([CH:40]=[O:41])[CH:35]=[CH:36][CH:37]=[CH:38][CH2:39]5)=[CH:30][C:29]=4[O:42][CH3:43])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 86.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanone as off-white crystals, m.p.=128°-130° C.
Reaction SMILES: CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:25][O:26][N:27]=[C:28]([C:33]1[NH:34][CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30].[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>CCOCC>[CH3:25][O:26][N:27]=[C:28]([C:33]1[N:34]([CH2:38][C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[CH3:41])[CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1ccccc1CBr
Reactant: CON=C(C(=O)OC)c1ccc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CON=C(C(=O)OC)c1cccn1Cc1ccccc1C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
4 g (35.7 mmol) of potassium tert-butylate are added to a solution of 730 mg (2.7 mmol) of 18-crown-6 in 50 ml of ether, after which a solution of 5 g (27.5 mmol) of the pyrrole from Example 18 in 50 ml of ether are added dropwise and stirring is carried out for 30 minutes at room temperature. Thereafter, a solution of 6.6 g (37.5 mmol) of o-methylbenzyl bromide in 25 ml of ether is addled and stirring is carried out overnight at room temperature. The mixture is poured onto water and extracted with ether, and the organic phase is dried and evaporated down. Chromatography over silica gel using hexane/ethyl acetate gives 4.1 g (52%) of the product as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:31]3[CH:32]=[CH:33][O:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccoc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccoc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and furan-3-carbaldehyde. MS (ESI) m/z 459.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[Br:13][CH2:14][C:15](Br)=[O:16]>>[Br:13][CH2:14][C:15]([O:3][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:16]
Reactant: O=C(Br)CBr
Reactant: COC(=O)[C@H](O)c1ccccc1
Product: COC(=O)[C@H](OC(=O)CBr)c1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To methyl (R)-mandelate (8.3 g, 150 mmol), and neutral alumina [e.g. Aldrich type WN-3] (17 g, 167 mmol) cooled with an ice-bath was added bromoacetyl bromide (44 mL, 500 mmol). The ice bath was removed and after 1 h standing at RT, the reaction mixture was poured onto solid NaHCO3 (117 g) in a glass filter funnel, with a cotton wool plug (effervescence). After standing overnight, the solid was washed with toluene until 200 ml of filtrate had been collected. The volatiles were removed via rotary evaporation to yield a crude product in 88% yield. This crude product was sufficiently pure to carry through to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19]>C1COCC1.CCOC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
To a 0° solution of 4′-aminoacetophenone (35 g, 259 mmol) in THF (400 mL) was added pyridine (26 mL, 324 mmol) and isobutyl chloroformate (37 mL, 285 mmol). The resulting heterogeneous mixture was stirred at 0° for 30 min and at room temperature for an additional 30 min. The reaction mixture was then diluted with EtOAc, washed serially with 10% (w/v) aqueous citric acid, 4 N aqueous HCl, H2O, saturated aqueous NaHCO3 and brine, then dried (MgSO4) and concentrated under reduced pressure to yield 2-methylpropyl N-(4-acetylphenyl)carbamate (65 g, quantitative yield) as an off white solid: 1H NMR (400 MHz, CDCl3) δ7.95 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.85 (s, 1H), 3.99 (d, 2H, J=6.7 Hz), 2.57 (s, 3H), 2.03 (m, 1H), 0.90 (d, 6H, J=6.7 Hz); MS (FAB) m/z 236 (MH)+. This product was used as such in the next reaction (section (b)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[N:3]=[CH:2]1.[H][H]>[Pd].C(OCC)(=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[N:3]=[CH:2]1
Reactant: CSCC[C@H](NC(=O)c1ccc(C=Cc2c[nH]cn2)cc1-c1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(CCc2c[nH]cn2)cc1-c1ccccc1)C(=O)O

Procedure:
The resultant olefin (1 mmol) from Example 48 is mixed with 5% palladium on carbon (100 mg) in ethyl acetate. The reaction mixture is attached to a hydrogenation apparatus, and then is detached from the apparatus after about 95% of the theoretical hydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo. The crude product is purified with a column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-:18].[K+].Cl>OCCOCCO.C(OCC)C>[CH2:1]([C:3]1[C:8]([C:9]([OH:18])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1c(C(N)=O)cccc1-c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCCOCCO
Solvent: CCOCC
Product: CCc1c(C(=O)O)cccc1-c1ccccc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
A stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.1 g, 0.0093 mole) and potassium hydroxide (26.3 g, 0.4 mole) in 175 ml of 2-hydroxyethyl ether was heated at 163° for approximately 18 hours. The reaction mixture was cooled and diluted with 150 ml of ice water. The solution was acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was isolated by filtration and dissolved in diethyl ether; the ethereal solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.2 g) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[F:20][C:21]1[N:22]=[CH:23][C:24]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3ccc(F)nc3)cc2)n1

Procedure:
2-[4-(6-Fluoro-pyridin-3-yl)-phenoxymethyl]-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 23 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-fluoropyridine-5-boronic acid (available from Frontier Scientific, Inc., Logan, Utah). Mass spectrum MH+=331.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[F:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:10][C:9](=[O:11])[CH2:8][C:6]2[C:5]([C:12]#[N:13])=[CH:4][C:3]([F:14])=[C:2]([Cl:1])[N:7]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: N#Cc1cc(F)c(Cl)nc1CC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: N#Cc1cc(F)c(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.05 h
Yield: 84.2 %

Procedure:
A homogeneous brown solution of (6-chloro-3-cyano-5-fluoro-pyridin-2-yl)-acetic acid (2.37 g, 11.0 mmol), as prepared in the previous step, 4-nitrophenol (1.84 g, 13.2 mmol), and DCM (11 mL) was stirred under argon at 0° C. while 1,3-diisopropylcarbodiimide (DIC) (1.90 mL, 12.1 mmol) was added dropwise with stirring over 3 min. The ice bath was immediately removed following completion of the DIC addition, and the brown mixture with yellowish precipitate was stirred at rt for 1 h 40 min. The crude reaction was then directly loaded onto a flash silica column and eluted with 96:4 toluene/CH3CN to afford the title compound as a translucent pale yellow oil (3.11 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 8.29 (m, 2H), 7.80 (d, 1H), 7.35 (m, 2H), 4.35 (d, 0.7 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]3([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:16]=2)=[CH:10][CH:9]=1)=O.Cl.[NH2:31][OH:32]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[N:31][OH:32])[C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]3([O:28][CH3:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:16]=2)=[CH:10][CH:9]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)c4nccs4)cc3)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)c4nccs4)cc3)c2)CCOCC1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl 2-thiazolyl ketone was reacted with hydroxylamine hydrochloride to give in turn the geometric isomers of 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl 2-thiazolyl ketone oxime:Isomer A in 40% yield, m.p. 153°-154° C.,
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10](Cl)(Cl)[CH:11]([OH:13])O.Cl.[NH2:17][OH:18].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH:10]=[N:17][OH:18]
Reactant: NO
Reactant: Nc1ccccc1Br
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccccc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a 1000 mL round bottom flask, 2-bromoaniline (15 g, 0.0872 mol), water (400 mL), chloral hydrate (17.05 g, 0.1046 mol), hydroxylamine hydrochloride (19.25 g, 0.279 mol) and sodium sulfate (57.81 g) were added. To this reaction mixture conc. HCl (21 mL) was slowly added. The reaction mixture was stirred at 100° C. for 3 h. The white precipitate was formed and was collected by filtration. The white solid was dried to get the title compound [7 g, 33%]. 1HNMR (300 MHz, DMSO-d6): δ 12.46 (s, 1H), 9.48 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.42 (t, J=6.9 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H); LC-MS (ESI): Calculated mass: 241.9; Observed mass: 243.0 [M+H]+ (RT: 0.66 min).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](N(CC)C)=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:50][CH2:51][CH2:52][CH2:53]C(Cl)=O>CN(C=O)C.CCOC(C)=O>[Br:50][CH2:51][CH2:52][CH2:53][C:32]([NH:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:23]2[N:24]=[C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:7][CH2:8]4)=[CH:17][CH:16]=3)[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=2)[CH2:26]1)=[O:33]
Reactant: CCN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncc(N2CCC[C@@H](NC(=O)CCCBr)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA (180 μL, 1.0 mmol) and then 4-bromobutyryl chloride (56 mg, 0.3 mmol). The mixture was stirred at RT for 1.5 hours, diluted with 60 mL EtOAc, washed with water ×3, dried, concentrated in vacuo to afford crude (R)-5-(3-(4-bromobutanamido)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (448). It was dissolved in 3 mL dry DMF and the solution was stirred at RT. To it was added NaH (60%, 30 mg), and the mixture was stirred for 1 hour. It was quenched with 0.5 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (449), as HCl salt (7 mg). LC-MS (ESI): m/z (M+1) 532.6. UV: λ=267, 275, 305, 335, 373 nm.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([CH2:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=O)C.C([O-])([O-])=O.[K+].[K+].CCOCC>CO.O>[OH:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([CH2:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC#N)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Temperature: 25 °C
Reaction time: 64 h
Yield: 96.9 %

Procedure:
A mixture of 581 mg (2.02 mmoles) of rac.-6-acetyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile and 418 mg (3.03 mmoles) of K2CO3 in 17 ml of methanol and 3 ml of water was stirred at room temperature for 64 hr. The resulting mixture was poured into water and worked-up with ether in the usual manner giving 480 mg of a tan solid. This material was triturated with cold ether to give 340 mg (69%) of a tan solid. A sample of this material was recrystallized from toluene yielding pure rac. 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a tan solid mp 162°-163°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH3:17][Mg]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([OH:15])([CH3:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C(Cn1ccnc1)c1cc(F)ccc1O
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Yield: 53.2 %

Procedure:
The general procedure of Example 1 was repeated using 1-(5-fluoro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-2)] and methylmagnesium bromide, to thereby yield 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol as colorless crystals (yield: 53.2%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].CS(O[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]#[N:30])[C:26]3[N:31]=[CH:32][N:33]([CH3:34])[C:25]=3[CH:24]=2)=[CH:19][C:18]=1[C:35]([F:38])([F:37])[F:36])(=O)=O>CN1C(=O)CCC1>[CH3:34][N:33]1[C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:3]4[CH2:4][CH2:5][O:1][C:2]4=[O:6])=[C:18]([C:35]([F:37])([F:38])[F:36])[CH:19]=3)[N:28]=[C:27]([C:29]#[N:30])[C:26]=2[N:31]=[CH:32]1
Reactant: O=C1NCCO1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCN4CCOC4=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
To oxazolidin-2-one (29.7 mg) in NMP (1 ml) was added sodium hydride is (60% in parafin oil, 13.6 mg). After stirring at room temperature for 10 minutes, 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (100 mg) was then added and the mixture was stirred at room temperature for 14 hours. The mixture was purified directly using HPLC to give 1-methyl-6-{4-[2-(2-oxooxazolidin-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (10 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: OCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 129.2 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 6-bromohexanol (54.3 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(6-hydroxyhexyloxy)benzoic acid (61.5 g, 86%). 4-(6-Hydroxyhexyloxy)benzoic acid (9.53 g), N,N-dimethylaniline (5.33 g) and dioxane (100 mL) were put into a 300-mL three-neck flask, and acrylic acid chloride (3.98 g) was gradually and dropwise added thereto at 60° C. and stirred for 6 hours. After cooled, this was poured into water with ice (200 mL), and the precipitated crystal was collected through filtration under suction, washed with hexane and dried to give TP-55C (9.4 g, 80%). Production of 2,3,6,7,10,11-hexa(4-(6-acryloyloxyhexyloxy)benzoyloxy)triphenylene (TP-55):