Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH:33]([F:35])[F:34])[CH:23]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:21].[OH-].[Na+].Cl>O1CCCC1.O>[F:35][CH:33]([F:34])[O:32][C:24]1[CH:23]=[C:22]([CH:5]([N:6]2[CH2:14][C:13]3[C:8](=[C:9]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:21])[CH2:4][C:3]([OH:36])=[O:2])[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([F:31])[F:30]
Reactant: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester (2.0 g, 4 mmol) in tetrahydrofurane (20 ml) was added NaOH (0.8 ml of 10 N) at room temperature. The solution was stirred overnight at room temperature. The resulted suspension was filtered to get a white solid. The solid was dissolved in water (30 ml) and added conc. HCl dropwise until the pH is about 4. The resulted mixture was extracted with CH2Cl2 (3×40 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid as a white solid (1.4 g, 70%): mp, 94-96° C.; 1HNMR (CDCl3) δ 0.86-0.93 (m, 2H, cyclopropyl ring CH2), 1.06-1.12 (m, 2H, cyclopropyl ring CH2), 1.65-1.71 (m, 1H, cyclopropyl ring CH), 3.13 (dd, J=6, 16 Hz, 1H, CHHCO), 3.32 (dd, J=9, 16 Hz, 1H, CHHCO), 4.15 (d, J=15 Hz, 1H, CHHN), 4.36 (d, J=15 Hz, 1H, CHHN), 5.78-5.84 (m, 1H, CHN), 6.21 (t, JH-F=75 Hz, 1H, OCF2H), 6.24 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=7.5 Hz, 1H, Ar), 7.26-7.28 (m, 3H, Ar), 7.44 (t, J=7.5 Hz, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.42 (s, 1H, NHCO); 13C NMR (CDCl3): 8.35, 8.38, 16.14, 36.55, 47.00, 51.29, 99.24, 111.36, 111.42, 115.60, 116.84, 117.02, 118.03, 119.74, 119.79, 121.59, 122.76, 125.46, 133.61, 137.09, 138.03, 141.12, 142.21, 142.38, 142.43, 169.63, 173.03, 173.82. Anal. Calcd. for C23H20F4N2O6: C, 55.65; H, 4.06; N, 5.64. Found: C, 55.33; H, 3.96; N, 5.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=1.Cl[C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-phenyl}-acetic acid methyl ester (0.076, 0.17 mmol) and methyl chloroformate (0.01 mL, 0.18 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.02 mL, 0.18 mmol), and the reaction was stirred at room temperature for 3 hours. Some starting material was still observed by analytical LCMS, so additional methyl chloroformate (0.02 mL) and triethylamine (0.03 mL) was added, and the reaction was stirred overnight. The mixture was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](I)[N:3]=1.[CH3:9][O-:10].[Na+].CO>O>[I:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: Ic1cncc(I)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cncc(I)n1
Yield: 100 %

Procedure:
2,6-Diiodopyrazine (5.0 g, 15 mmol) was added to a solution of sodium methoxide in methanol (prepared from sodium (0.35 g, 15 mmol) and methanol (40 ml)) and the mixture was heated at reflux temperature for 1 hour. After cooling, the solution was diluted with water (200 ml) and extracted with diethylether (3×100 ml). The combined extracts were washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give the product as a white solid (3.5 g, 100%) m. pt. 35.7-37.2
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)#[N:2].[O:8]1CCC[CH2:9]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][N:5]1[CH:6]=[CH:7][C:3]([C:1]#[N:2])=[CH:4]1
Reactant: N#Cc1cc[nH]c1
Reactant: C1CCOC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: N#Cc1ccn(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
670 mg of 3-cyano-1H-pyrole, 10 ml of tetrahydrofuran and 10 ml of formaldehyde 36% in water were mixed. 0.1 ml of tetrabutylammonium hydroxide 10% in water was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-cyano-1H-pyrole.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:11]1([CH2:18][CH:19]=[CH2:20])[CH2:15][NH:14][C@@H:13]([CH2:16][OH:17])[CH2:12]1)[CH:9]=[CH2:10].[S:21](Cl)(Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH2:18]([C:11]1([CH2:8][CH:9]=[CH2:10])[CH2:15][N:14]2[S:21](=[O:23])(=[O:22])[O:17][CH2:16][C@H:13]2[CH2:12]1)[CH:19]=[CH2:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CCC1(CC=C)CN[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(CC=C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A solution of triethylamine (2.460 ml, 17.65 mmol) and (R)-(4,4-diallylpyrrolidin-2-yl)methanol (1.60 g, 8.83 mmol) in DCM (44.1 ml) was cooled to −78° C. To this mixture was added sulfuryl chloride (0.859 ml, 10.59 mmol) in DCM (44 mL) dropwise in 1 h. The reaction was maintained at this temperature for 3 h, then allowed to warm to room temperature and stirred overnight. The mixture washed with aq. 1 N HCl (30 ml×2), brine (30 ml), dried, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (0.66 g, 2.71 mmol, 30.7% yield) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.71-5.86 (m, 2H), 5.10-5.20 (m, 4H), 4.57 (dd, J=6.63, 8.76 Hz, 1H), 4.24-4.36 (m, 1H), 4.19 (dd, J=4.66, 8.76 Hz, 1H), 3.21-3.32 (m, 2H), 2.19-2.29 (m, 4H), 2.03-2.18 (m, 1H), 1.57-1.63 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:20]([C:14]2[C:15](=[O:19])[NH:16][C:17]3[C:12]([C:13]=2[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:18]=3)=[O:22])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NC1CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.80 (1H, br), 10.35 (1H, br), 8.35 (1H, br), 7.38 (1H, s), 7.30 (2H, m), 7.15 (2H, t, J=8.7 Hz), 4.06 (2H, br s), 2.85 (1H, m), 0.74 (2H, m), 0.51 (2H, m); HRMS calcd for C19H16FN3O3+H+: 354.1254. Found: 354.1255.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]
Reactant: OCCc1ccccn1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCc2ccccn2)cccc1[N+](=O)[O-]
Yield: 82 %

Procedure:
Prepared as in Example 187c from 2-(pyridin-2-yl)ethanol and 2,6-dinitrobenzonitrile in 82% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, J=6.4 Hz, 2H), 4.64 (t, J=6.4 Hz, 2H), 7.23-7.27 (m, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.71-7.79 (m, 2H), 7.86-7.91 (m, 2H), 8.50-8.52 (m, 1H). MS 270 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncco2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ncco2)c1
Temperature: 80 °C

Procedure:
To a slurry of stannous chloride dihydrate (11.8 g, 0.05 mol in 35 mL of ethyl acetate under argon at room temperature was added 2-(3-nitro-phenyl)1,3-oxazole (1.95 g, 0.01 mol, from part A). After heating at 80° C. for 20 minutes, the mixture was poured onto crushed ice and made basic (pH 8.5) with saturated sodium bicarbonate. After filtering the resulting solution through a pad of celite to remove insolubles, the organic layer was separated, washed with water and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 1.64 g of an oil that slowly solidified. 13C-NMR (CDCl3) δ162.1,146.8, 138.3, 129.7, 128.2, 117.0, 116.5, 112.5. m/s (m+H)+ @ 161; MW=160.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.NC(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
2-chloro-5-methoxycarbonylpyridine (7.0 g) and urea-hydrogen peroxide adduct (6.93 g) were suspended in acetonitrile (100 mL), and trifluoroacetic anhydride (9.92 mL) was dropwise added thereto at 0° C. The reaction mixture was stirred at room temperature for 5 hours, and evaporated in vacuo to remove the solvent. After addition of saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate to the residue, the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The organic solvent was evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:8) to give the title compound as a pale brown solid (8.0 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:19]([Cl:21])=[O:20])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-t-butyl-5-(methylthio)pyrazole (10 g), and triethylamine (6.0 g) were added dropwise at -20° to a stirred solution of phosgene (7.5 ml) in tetrahydrofuran (75 ml). The solution was allowed to come to room temperature, and was then stirred for 2 hours. Excess phosgene was removed by drawing dry air through the mixture for 1/2 hour. The reaction mixture was filtered, and evaporated to give a yellow oil which quickly crystallised. Recrystallisation from petrol gave 3-tert-butyl-1-chlorocarbonyl-5-(methylthio)pyrazole, 5.0 g (64% yield), melting point 64°-6°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.O>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:10][C:9]1=2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a solution of 0.46 gram (2.85 mmole) 6-amino-3,4-dihydro-2H-naphthalen-1-one in 25 mL pyridine was added 0.605 grams (3.42 mmoles) benzenesulfonyl chloride. The reaction mixture was stirred at 23° C. for 24 hours. The mixture was diluted with 100 mL water and extracted with 200 mL ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 50% ethyl acetate in hexane. The title compound was obtained as a solid, 0.48 gram (56%), m.p. 164-165° C., M−H=300.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH:16]([C:17](=[O:27])[CH2:18][P:19]([O:24]CC)([O:21]CC)=[O:20])[CH2:15][CH2:14][CH2:13][N:12]1C(OCC1C=CC=CC=1)=O)=[O:10])C1C=CC=CC=1.Cl.C(O)C>C(O)(C)C>[P:19]([CH2:18][C:17]([CH:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH:11]1[C:9]([OH:10])=[O:8])=[O:27])([OH:21])([OH:24])=[O:20]
Reactant: CCOP(=O)(CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1C(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: O=C(CP(=O)(O)O)C1CCCNC1C(=O)O
Yield: 91.1 %

Procedure:
Mix N-carbobenzoxy-3[(diethoxyphosphinyl)acetyl]piperidine-2-carboxylic acid benzyl ester (3.6 g) and 6N hydrochloric acid (400 mL) and reflux for 24 hours. Condense with a stream of nitrogen and dissolve the residue in a mixture of absolute ethanol (75 mL) and isopropanol (75 mL). Filter and add propylene oxide until a white precipitate develops. Filter the precipitate, wash with isopropanol and dry to give the title compound as a white powder (1.55 g, 91%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]#[N:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]#[N:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CC#N
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#CCn1c(C(=O)O)cc2cc(Cl)ccc21
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 1.0 eq. of 5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (prepared according to Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1989), 28B(12), 1065-8) in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at R/T, acidified to pH2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a light yellow solid (84%).
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[F:38][C:39]1[CH:44]=[C:43]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:35])[F:34])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)[CH:42]=[CH:41][CH:40]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(F)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1cc(Cl)cc(-n2ncc3c(I)ccnc32)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1cc(F)cc(Cl)c1
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 75A (558.6 mg, 1.46 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569.2 mg, 2.24 mmol), potassium acetate (584.3 mg, 5.95 mmol), and anhydrous DMSO (11 mL). The reaction mixture was flushed with argon and treated with PdCl2(dppf).CH2Cl2 (59.1 mg, 0.081 mmol). The reaction mixture was heated to 85° C. for 1 h and then at 105° C. for 1.5 h to give conversion to the desired product. LC/MS (Condition B): ret. T=4.29 min, (M+H)+ 291.99, 292.99.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (25.0 g, 104.9 mmol) in DMF (500 mL), potassium carbonate (58 g, 420 mmol) and benzyl bromide (14.9 mL, 126 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to give titled material.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:17][CH3:18])[N:3]=1.N.COCCOCC[N:27](CCOCCOC)CCOCCOC>[Cu].CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:27])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:17][CH3:18])[N:3]=1
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: CSc1nc(N)nc(Cl)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: N
Solvent: CCO
Product: CSc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl
Temperature: 180 °C
Yield: 1181.2 %

Procedure:
A mixture of 2-amino-4-chloro-5-(2,4-dichlorophenyl)-6-methylthio pyrimidine (0.5 g) (Example 32) EtOH saturated with ammonia (20 ml), copper powder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.01 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.11 g, 23.5%), mp. 191°-192° C. Microanalysis:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(=O)OCC>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: Clc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (60 mg, 0.3 mmol), 1-(2-chlorophenyl)piperazine (70 mg, 0.31 mmol), and D1 EA (110 μL, 0.66 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.12 (m, 4H) 4.06 (s, 2H) 7.03 (m, 1H) 7.19 (m, 1H) 7.29 (m, 1H) 7.39 (dd, J=7.96, 1.40 Hz, 1H) 7.54 (dd, J=8.11, 4.68 Hz, 1H) 8.31 (dd, J=8.11, 1.56 Hz, 1H) 8.58 (dd, J=4.68, 1.56 Hz, 1H) (ESI) m/z 345 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)=[O:4].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11](=[NH:12])[NH:14][OH:15])=[N:7][CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1cnc(C#N)nc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C(=N)NO)nc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of 2-cyano-pyrimidine-5-carboxylic acid methyl ester 3 (1 g, 6.13 mmol) in MeOH (20 mL) at room temperature is added hydroxylamine hydrochloride (0.64 g, 9.2 mmol) and sodium acetate (0.76 g, 9.2 mmol). The resulting mixture is heated to reflux for 2 hours. The mixture is cooled to room temperature and concentrated in vacuo. Water (30 mL) is added to the residue, and the solid is filtered, and washed with water twice. The solid is dried in vacuum oven overnight to afford 2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl ester (1.09 g, 91%) as a solid. MS: 197 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.S(=O)(=O)(O)O.O.[C:20](=O)([O-])[O-].[K+].[K+]>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:20])=[O:12])=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1n[nH]c2ncccc12
Temperature: 70 °C

Procedure:
2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetic acid (317 mg a crude) was dissolved in 15 mL methanol, and concentrated sulfuric acid 0.5 mL was added dropwise. It was heated to 70° C. and reacted for 12 hours. The reaction was monitored to be complete by LC-MS. 50 mL water was added, and the pH was adjusted to be weak basic with potassium carbonate. Methanol was rotate evaporated. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotate evaporated to dryness to obtain a light yellow solid 250 mg, at a yield over two steps of 73.6%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1Cl>O1CCOCC1>[CH2:20]([CH:19]1[C:13]2[CH:12]=[C:11]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[CH:15][C:14]=2[C:17](=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]2=[O:31])[O:18]1)[CH3:21]
Reactant: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)c(Cl)c21
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(NCCN3CCOCC3)cc21
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (320 mg, 2.46 mmol) in 3 mL of dioxane is treated with 3-(6,7-Dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.32 mmol) in one portion and the reaction mixture is heated at 100° C. until no starting material remains. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, 5% MeOH-EtOAc) to give the title compound as a solid (36 mg, 28%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([Cl:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CCOc1cccc(Cl)c1-c1ccccc1C
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc(Cl)c(-c2ccccc2C)c1O
Yield: 75 %

Procedure:
A solution of 2-allyloxy-6-chloro-2′-methylbiphenyl (4.0 g, 15.4 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 3.0 g (75%) of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol as a light yellow oil.