Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([C:37]2[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C@@H:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:20][C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=3[CH3:22])[CH:19]=[CH:18][CH:17]=2)=[CH:29][CH:28]=1)[C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[CH3:36]
Reactant: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Reactant: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1nccn1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Cs2CO3 (72 mg, 0.22 mmol) and compound 9.9 (53 mg, 0.21 mmol) were added successively to a solution of (S)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.6) (55 mg, 0.2 mmol) in dry DMF (3 mL). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (60 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was flash chromatographed on silica gel (0-5% MeOH in DCM) to afford (S)-ethyl 3-(4-[3-(4-chloro-2-methylphenyl)benzyloxy]phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.10) as a colorless oil (97 mg). LC-MS ESI (pos.) m/e: 489 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[F:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:32][C:31]=1[F:37])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccc(OCc2ccccc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.59 g of pyrazine-2-carboxylic acid and 4.73 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (60 ml) solution of 4.13 g of 4-benzyloxy-3-fluoroaniline, and the reaction liquid was stirred overnight at room temperature. Pyridine was evaporated away under reduced pressure, and then water was added to it. The resulting deposit was taken out through filtration to obtain the entitled compound as a brown solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21]3([CH3:24])[CH2:23][CH2:22]3)[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Pt](=O)=O>[C:21]([C:13]1[C:12]2[C@@H:25]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=3)[O:26][C:27]3([CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:11]=2[C:10]2[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[N:14]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)Cc2nc(C3(C)CC3)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)Cc2nc(C(C)(C)C)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
30 mg (3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-4-(1-methylcyclopropyl)-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran] are dissolved in 3 ml acetic acid and 1 ml acetic acid anhydride. 30 mg Platinum-(IV)-oxide are added and the mixture is hydrogenated for 2 hours at 60° C. and 3 bar. The catalyst is filtered off and washed with methanol. The liquid phases are combined and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Reactant: Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1[C@H]1CC[C@](O)(C(F)(F)F)Cc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
1 M lithium bis(trimethylsilyl)amide in toluene (0.24 mL, 0.24 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 0.07 mmol) and 2-methylpyridin-3-amine (0.012 g, 0.11 mmol, Appollo) in THF (2 mL) at about 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (0.008 g, 0.07 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.07 mL, 0.07 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM). The appropriate fractions were concentrated in vacuo. The product was recrystallized from Et2O to give rac-4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.005 g, 12%): LC-MS (Table 1, Method g) Rt=1.86 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.85 (s, 1H), 8.44-8.41 (m, 1H), 8.32-8.29 (m, 1H), 7.82-7.78 (m, 1H), 7.75-7.67 (m, 3H), 7.60-7.56 (m, 1H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.61-5.55 (m, 1H), 3.93 (s, 3H), 3.40-3.32 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.36-2.26 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.71 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][CH:12]=3)([CH2:8]2)[CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1COCC1.O>[CH2:39]([O:38][C:36](=[O:37])[O:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][CH:12]=3)([CH2:8]2)[CH2:6]1)=[O:4])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)CO)C4)cc2)C(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)OCC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Yield: 29.9 %

Procedure:
To a solution of N-(3-{4-[3-(2-hydroxy-acetyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-phenyl}-2-oxo-oxazolidin-5(S)-ylmethyl)-acetamide (Example X) (200 mg, 0.54 mmol) in THF (5 mL) were added triethylamine (0.19 mL, 1.35 mmol) and ethyl chloroformate (0.07 mL, 0.7 mmol) at 0° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (72 mg, 30%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:16])([CH:13]([F:15])[F:14])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:9][C:10]([F:16])([CH:13]([F:15])[F:14])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(O)c1
Reactant: FC(F)C(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(F)(F)C(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) in N,N-dimethylformamide (50 ml) were added 2,2,3,3-tetrafluoro-1-iodopropane (12.3 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol) and the mixture was stirred overnight at 80° C. The reaction solution was diluted with water (200 ml) and extracted with diethyl ether (300 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(2,2,3,3-tetrafluoropropyloxy)toluene (10.0 g, 97%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5]1)[C:2]#[CH:3].CO.[C-:13]#[N:14].[Na+]>[C-]#N.[Na+].O.C(O)(=O)C>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][N:4]([CH2:1][C:2]#[CH:3])[CH:5]=1)[C:13]#[N:14]
Reactant: [C-]#N
Reactant: C#CCn1ccc(CO)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C#CCn1ccc(C(O)C#N)c1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
0.44 ml of acetic acid was added to a solution of 510 mg of the product of Step B of Example 1, 7 ml of methanol and 2 ml of water another 0.44 ml of acetic acid was added. The mixture was cooled to 20° C. and 2.82 mg of sodium cyanide were added, after which the mixture was stirred for 90 minutes at 20° C., then cooled to ±10° C. Another 1.4 g of sodium cyanide and 2.2 ml of acetic acid were added and after stirring for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and dried, then concentrated to dryness to obtain 590 mg of α-hydroxy-1-(2-propynyl)-1H-pyrrole-3-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][CH2:24][C:25]1[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[NH:27][C:26]=1[CH3:33].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:23][CH2:24][C:25]1[C:30](=[O:31])[CH:29]=[C:28]([CH3:32])[NH:27][C:26]=1[CH3:33])=[O:9]
Reactant: Cc1c(O[C@H]2CC[C@H](N(C)C)CC2)cc(Cl)cc1C(=O)O
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(O[C@H]3CC[C@H](N(C)C)CC3)c2C)c(C)[nH]1
Reaction time: 16 h

Procedure:
A 20 mL vial was charged with 5-chloro-3-(((trans)-4-(dimethylamino)cyclohexyl)oxy)-2-methylbenzoic acid (120 mg, 0.385 mmol), 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one, hydrochloride (80 mg, 0.423 mmol), EDC (111 mg, 0.577 mmol), HOAT (89 mg, 0.577 mmol), N,N-dimethylformamide (DMF) (3 mL), and NMM (1.015 mL, 9.24 mmol). The reaction was stirred for 16 h, at which time it was poured into a stirring solution of water (5 mL) and sat Na2CO3 (20 mL). The mixture was stirred at room temperature 1 h, but no precipitate had formed. EtOAc was added and the layers were separated. White precipitate formed in the aqueous layer. The precipitate was filtered and determined to not be the title product. LCMS showed the product in both layers, so the layers were re-combined and concentrated in vacuo. The solid residue was diluted with MeOH (3 mL) and DMSO (1 mL) and the insolubles were filtered off. The solution was purified by reverse phase HPLC (Phenomenex Gemini-NX axia 30×100 mm, 5μ, C18; 15-45% acetonitrile/0.1% formic acid in water). Since the product was running close to the solvent front, the gradient was changed to 5-45% 0.1% formic acid in water/acetonitrile and the remaining sample was purified by this method. The desired fractions were concentrated to a glassy solid. The residue was dissolved in MeOH (3 mL) and filtered through ISOLUTE® Si-Carbonate (2 g) to remove the formic acid. The ISOLUTE® Si-Carbonate was washed with MeOH (3 mL) and the combined methanol layers were concentrated in vacuo. The ISOLUTE® Si-Carbonate filtration step was repeated and the MeOH washing concentrated in vacuo to give 5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-3-(((trans)-4-(dimethylamino)cyclohexyl)oxy)-2-methylbenzamide (45 mg, 0.100 mmol, 26.0% yield), as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (br. s., 1H), 8.22 (br. s., 1H), 7.11 (d, J=2.02 Hz, 1H), 6.78 (d, J=1.77 Hz, 1H), 5.87 (br. s., 1H), 4.27-4.41 (m, J=4.52, 4.52, 8.40 Hz, 1H), 4.19 (d, J=5.05 Hz, 2H), 2.31 (s, 3H), 2.17-2.21 (m, 1H), 2.17 (s, 6H), 2.16 (s, 3H), 2.03 (s, 5H), 1.78 (br. s., 2H), 1.37 (t, J=9.98 Hz, 4H). MS(ES) [M+H]+ 446.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]2[CH2:42][CH2:43][CH2:44][C@H:40]2[CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC[C@H]3CN3CCCC3)c1C)C(=O)N2

Procedure:
5-[5-(2,6-Dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (50 mg, 1.2 eq.), HOBt (42 mg, 1.2 eq.), EDAC.HCl (60 mg, 1.2 eq.) and TEA (3 eq.) in acetonitrile: DMF (3:1) to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:5]2[N:6]([C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 g of ethyl 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 15A; 115.5 mmol, 1 equivalent) were dissolved in 550 ml of THF and 700 ml of methanol, 13.8 g of lithium hydroxide (dissolved in 150 ml of water; 577 mmol, 5 equivalents) were added and the mixture was stirred at RT overnight. 1 N aqueous hydrochloric acid was added to the reaction mixture, and the mixture was concentrated. The solid obtained was filtered off and washed with water. This gave 34 g of the title compound (84% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:11][C:10]2[NH:24][N:25]=[C:26]([CH3:27])[C:9]1=2>ClCCl.CO.[O-2].[Mn+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:11]=[C:10]2[NH:24][N:25]=[C:26]([CH3:27])[C:9]=12
Reactant: COc1ccc(C2=C(C#N)C(c3ccccc3F)c3c(C)n[nH]c3N2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2nc3[nH]nc(C)c3c(-c3ccccc3F)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
5.43 g (62.4 mmol) of manganese oxide is added to 4.5 g (12.49 mmol) of 4-(2-fluorophenyl)-6-(4-methoxyphenyl)-3-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in solution in 60 ml of dichloromethane and 15 ml of methanol. The reaction mixture is placed in an ultrasonic bath for 5 minutes and then stirred at room temperature for 20 hours before being filtered on Dicalite. The filtrate is evaporated to yield 4.1 g (92%) of 4-(2-fluorophenyl)-6-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(Cl)[C:10](=[CH:14][C:15](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[N+:16]([O-:18])=[O:17])[N+:11]([O-:13])=[O:12]>[Cu]>[N+:21]([C:20]1[CH:19]=[C:15]([N+:16]([O-:18])=[O:17])[CH:14]=[C:10]([N+:11]([O-:13])=[O:12])[C:9]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Cu]
Product: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1). C 7 ⁢ H 7 ⁢ I + C 6 ⁢ H 2 ⁢ Cl ⁢ N 3 ⁢   ⁢ O 6 ⁢ → Δ Cu ⁢ C 13 ⁢ H 9 ⁢ I 3 ⁢ N 3 ⁢   ⁢ O 6 2′,4′,6′-trinitro-4-methylbiphenyl (1) is reacted with stannous chloride and hydrochloric acid to yield 2′,4′,6′-triamino-4-methylbiphenyl (2). C 13 ⁢ H 9 ⁢ N 3 ⁢   ⁢ O 6 ⁢ → H ⁢   ⁢ Cl Sn ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 15 ⁢ N 3 2′,4′,6′-triamino-4-methylbiphenyl (2) is reacted with sodium nitrite and hydrochloric acid to convert the amino groups to diazonium groups. The diazonium groups react with potassium iodide to yield 2′,4′,6′-triiodo-4-methylbiphenyl (3). C 13 ⁢ H 15 ⁢ N 3 ⁢ → H ⁢   ⁢ Cl Na ⁢   ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ I ⁢   ⁢ C 13 ⁢ H 9 ⁢ I 3 Aromatic nitration of 2′,4′,6′-triiodo-4-methylbiphenyl (3) is performed with nitric acid and sulfuric acid to yield a mixture of 2′,4′,6′-triiodo-2-nitro-4-methylbiphenyl (4) and 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5). The products are separated using column chromatography. C 13 ⁢ H 9 ⁢ I 3 ⁢ → H 2 ⁢   ⁢ S ⁢   ⁢ O 4 H ⁢   ⁢ N ⁢   ⁢ O 3 ⁢ C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 The methyl group of 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5) is oxidized by potassium permanganate to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6). C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ Mn ⁢   ⁢ O 4 ⁢ C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 5 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 The hydroxyl groups of D-Glucosamine (8) are protected by reaction with acetic anhydride in the presence of pyridine to yield 1,3,4,6-tetra-O-acetyl-D-glucosamine (9). C 6 ⁢ H 13 ⁢ N ⁢   ⁢ O 5 ⁢ → C 5 ⁢   ⁢ H 5 ⁢ N C 4 ⁢   ⁢ H 6 ⁢   ⁢ O 3 ⁢ C 14 ⁢ H 21 ⁢ N ⁢   ⁢ O 9 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7) to yield 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10). C14H21NO9+C13H5ClI3NO3→C27H25I3N2O12 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10) is treated with stannous chloride in the presence of hydrochloric acid to yield 2-amino-4-(2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (11). C 27 ⁢ H 25 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 19 ⁢ H 19 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CS(C)=O>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCCn1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(NCCCn2ccnc2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 137.5 g 1-(3-aminopropyl)imidazole were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The precipitated product was suction-filtered and dried overnight under vacuum.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cl-:12].[Li+]>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Cl:12])=[N:3][CH:4]=1
Reactant: [Cl-]
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Li+]
Product: O=[N+]([O-])c1cc(Br)cnc1Cl

Procedure:
5-Bromo-2-chloro-3-nitropyridine was prepared according the method described by K. Jouve and J. Bergman, J. Heterocyclic Chem., 40, 261 (2003) from 2-amino-5-bromo-3-nitropyridine except that one equivalent of lithium chloride was added and the yield was improved to 84%. The required product gave the characterising data:—1H NMR Spectrum: (CDCl3) 8.70 (1H, d); 8.37 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.C(=O)([O-])[O-].[K+].[K+].Br[C:54]1[CH:55]=[CH:56][C:57]([CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[N:58][CH:59]=1>[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].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]>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:54]1[CH:55]=[CH:56][C:57]([CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[N:58][CH:59]=1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNC(=O)OC(C)(C)C)nc3)c2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1,1,1-trifluoromethanesulfonic acid 6-methoxy[1,5]naphthyridin-4-yl ester (2.0 g, 8.42 mmole) in dry dioxane,(75 mL) at RT was added bis(pinacolato)diboron (2.14 g, 8.43 mmole), potassium acetate (1.91 g, 19.4 mmole), 1,1-bis(diphenylphosphino)ferrocene (0.18 g, 0.32 mmole) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.26 g, 0.32 mmole). The reaction contents were heated to 80° C. for 24 h under nitrogen gas and then 1,1-bis(diphenylphosphino)ferrocene (0.18 g, 0.32 mmole), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.26 g, 0.32 mmole), potassium carbonate (2.68 g, 19.44 mmole) and 1,1-dimethylethyl [2-(5-bromo-2-pyridinyl)ethyl]carbamate (1.94 g, 6.48 mmole) were added to the reaction pot. After 24 h of vigorous stirring at 80° C., the reaction contents were filtered through a scinter-glass funnel containing a bed of celite (EtOAc). The filtrate was concentrated under vacuum and purified on silica (EtOAc) to afford the title compound (1.52 g, 62%) as a tan solid: LC-MS (ES) m/e 381 (M+H)+.