Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl (trans)-4-aminocyclohexylcarbamate (1.500 g) and triethylamine (2.93 mL, 2.125 g) were added to dichloromethane and stirred until the tert-butyl (trans)-4-aminocyclohexylcarbamate had dissolved completely. Acetyl chloride (0.577 g) was added slowly, and the solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue taken up in ethyl acetate, washed with pH 4 buffer, washed with brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: Nc1cccc(Br)c1
Product: Cc1cn(C)c2c(Nc3cccc(Br)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and 3-bromoaniline (74 ul) to give 1-[7-(3-bromo-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (93 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1>>[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([NH:18][C:16]([C:15]2[C:9]3[N:8]=[C:7]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[NH:11][C:10]=3[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:37])([F:38])[F:39])=[O:29])[CH:14]=2)=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: COCCN
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Product: COCCNc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1

Procedure:
2-Methoxyethylamine (2 mL) was added to 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (40 mg, Example 135). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 17 hours. The reaction mixture was washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (35 mg) as white powder. This was dissolved in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (28 mg) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:11][OH:12].C[O-].[Na+]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:11][OH:12])[NH2:5]
Reactant: N#Cc1ccccc1O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccccc1O

Procedure:
2-Hydroxybenzonitrile (10 grams), hydroxylamine HCl in 150 ml. ethanol, and sodium methoxide (9.0 grams) were refluxed for about 18 hours. The reaction mixture was then filtered and the ethanol evaporated. Next water was added and extracted into ethyl acetate. Drying and evaporation of the solvent left on oily product which solidified upon standing. The identity of the final product was confirmed by NMR and IR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C@H:12](O)[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:11]([C@@H:12]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](O)c1cc2ccc(F)cc2nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of (R)-1-(2-chloro-7-fluoroquinolin-3-yl)ethanol (3.03 g, 13.4 mmol), phthalimide (2.37 g, 1.20 eq) and PPh3 (4.23 g, 1.20 eq) in THF (70 mL) was added DIAD (3.13 mL, 1.20 eq) dropwise at 0° C. The mixture was then stirred at rt overnight before partitioning between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (DCM) to give a white foam of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (3.8 g, 80%). Mass Spectrum (ESI) m/e=355 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:53]=[CH:54][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:56][N:57]=1
Reactant: COc1ncc(-c2cccc(N)c2)cn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyrimidin-5-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.012 g of product in 48% yield: LCMS (ESI) m/z 404 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:14][CH3:15].Cl>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 70.4 %

Procedure:
A solution of 6-bromoindole (1.01 g, 5.15 mmol) in THF (10 mL) was cooled in an ice bath. Sodium hydride (0.459 g of 60% dispersion in oil, 11.5 mmol) was added. After stirring for 35 minutes at room temperature under nitrogen, the reaction mixture was again cooled in an ice bath, and iodoethane (0.90 mL, 11 mmol) was added. The mixture was stirred for 2 hours at room temperature, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane as an eluant to yield 6-bromo-1-ethyl-1H-indole (0.812 g, 71%) as a yellow oil. 1HNMR (300 MHz, DMSO-d6): δ7.75 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.45 (d, 1H, J=3.9 Hz), 7.15 (dd, 1H, J=7.8 Hz and 1.6 Hz), 6.45 (s, 1H), 4.2 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=O)[O:18]C2C=CC([N+]([O-])=O)=CC=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.O>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][C:17](=[O:18])[O:16][C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[CH2:3]1
Reactant: O[C@H]1CCOC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
(S)-(+)-3-Hydroxy-tetrahydrofuran (0.88 mL, 13 mmol) was dissolved in DCM (5 mL) and H2O (40 mL), carbonic acid bis-(4-nitro-phenyl) ester (5.8 g 19 mmol) and TEA (2.8 mL, 20 mmol) were added slowly. The reaction was allowed to stir at room temperature for 24 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give carbonic acid 4-nitro-phenyl ester tetrahydro-furan-3-yl ester as light yellow solid (2.3 g, 71%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18]1C=C([CH:22]=[C:23]([F:25])[CH:24]=1)N)([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[C:13]([O:17][C:18]1[CH:11]=[C:12]([N:8]=[C:1]=[S:2])[CH:22]=[C:23]([F:25])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)Oc1cc(N)cc(F)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved in dichloromethane (3200 ml). The mixture was stirred under N2 atmosphere while a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) in dichloromethane (800 ml) was added slowly within 2 h. Then the mixture was kept stirring at 20° C. for 16 h. The mixture was diluted with water (3000 ml). The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to remove solvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g). 1H-NMR (400 MHz, CDCl3): 6.63-6.68 (m, 3H), 1.37 (s, 9H).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:68]([NH:72][CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70].C(N(CC)CC)C>C(Cl)Cl>[CH2:68]([N:72]([C:55](=[O:56])[C:54]([C:51]1[CH:52]=[C:53]2[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:46]([C:60]3[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=3)[NH:47][C:48]2=[N:49][CH:50]=1)([CH3:59])[CH3:58])[CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N(CC(C)C)CC(C)C)cc3c2[C@H](C)COCc2ccccc2)c1
Reaction time: 12 h

Procedure:
PyBOP is added to a stirred mixture of (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoic acid, diisobutylamine and triethylamine in CH2Cl2 at ambient temperature. After approximately 12 h, the reaction mixture is poured into waterlbrine (1:1) and extracted with ethyl acetate. The combined organic extract is washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (gradient elution; 60-75% ethyl acetate/hexanes as eluent) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[NH3:25]>>[CH:18]([O:17][P:15](/[CH:14]=[CH:13]/[CH2:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:25])([O:21][CH:22]([CH3:24])[CH3:23])=[O:16])([CH3:20])[CH3:19]
Reactant: N
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)ncnc21)OC(C)C
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)ncnc21)OC(C)C
Yield: 70 %

Procedure:
A solution of (E)-6-chloro-9-[4-(diisopropoxy-phosphoryl)but-3-enyl]purine (309 mg, 829mmol) in saturated ethanolic ammonia (35 ml) was heated at 80° C. in a stainless steel autoclave for 5 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with ethyl acetate-methanol (3:1) to give (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyl]adenine as a white solid (205 mg, 70%), m.p. 121°-122° C.; λmax (EtOH) 262 (11,855)nm; υmax (KBr) 3320, 3175, 2935, 1650. 1600, 1575, 1475 and 1240 cm-1 ; δH (CDCl3) 1.25 (12H, dd, J 6 Hz and 19 Hz, CH(CH3)2), 2.84 (2H, m, CH2), 4.35 (2H, t, J 7 Hz, CH2N), 4.55 (2H, m, CH(CH3)2), 5.69 (1H, dd, J 17 Hz and 19 Hz, PCH=CH), 5.76 (2H, s, NH2), 6.70 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH ), 7.79 (1H, s, H-2/H-8), 8.37 (1H, s, H-2/H-8) (Found: MH+ 354.1695. C15C24N5O3P requires MH+ 354. 1695).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=2)[OH:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCOCCc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)c(OCc2ccccc2)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
To a tetrahydrofuran solution (6 mL) of 1-bromo-4-[2-(methoxymethoxy)ethyl]benzene (1.52 g, 6.20 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (2.38 mL, 6.20 mmol), and the mixture was stirred for 10 minutes at the same temperature. Then a tetrahydrofuran solution (6 mL) of 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde (2.02 g, 6.20 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (750 mg, 25%) as a colorless oily compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:34][C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)nc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6-chloropyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-chloropyridin-3-yl)terephthalamide. MS (Q1) 497 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[N:6][CH:7]=1.[N+](C1C=CC(S(O[CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:42][C:40]1([F:43])[CH2:41][C@@H:39]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)cn3)nc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OC[C@H]4CC4(F)F)cn3)nc2cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A suspension of N-((2S)-1-((2-(5-hydroxypyridin-2-yl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (37.4 mg), ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (50.1 mg) and potassium carbonate (31.5 mg) in DMF (5 mL) was stirred at 70° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title m compound (12.4 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14](F)[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1.CC1(C)O[C@@H]2C=C[C@@H]([N:31]3C4C(F)=NC=C(F)C=4N=C3)[C@@H]2O1>N>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:10]3[C:18]4[C:17]([F:19])=[CH:16][N:15]=[C:14]([NH2:31])[C:13]=4[N:12]=[CH:11]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)C=C[C@H]2O1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)C=C[C@H]2O1
Agent: N
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C=C[C@H]2O1
Temperature: 85 °C

Procedure:
Liquid ammonia (30 mL) was added to a mixture of 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (2-2) (160 mg, 0.55 mmol, 1 equiv) and 3-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-3H-imidazo[4,5-c]pyridine (2-1) (160 mg, 0.55 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 85° C. for 4 days. The mixture was then concentrated and purified via flash chromatography on a 40 g silica gel column (gradient elution 0 to 100% ethyl acetate in dichloromethane and then 100% methanol to elute 2-3) to yield 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-1H-imidazo[4,5-c]pyridin-4-amine (2-3) as a light yellow solid in addition to 3-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3 aH-cyclopenta[d][1,3]dioxol-4-yl]-7-fluoro-3H-imidazo[4,5-c]pyridin-4-amine (2-4) and recovered starting material 2-2. 1H NMR (2-3) (500 MHz, CDCl3): δ 7.76 (d, J=3.0 Hz, 1H); 7.63 (s, 1H); 6.36 (d, J=5.7 Hz, 1H); 6.03 (d, J=5.7 Hz, 1H); 5.68 (s, 1H); 5.42 (d, J=5.6 Hz, 1H); 5.03 (s, 2H); 4.68 (d, J=5.7 Hz, 1H); 1.50 (t, J=9.7 Hz, 3H); 1.42-1.33 (m, 3H). LRMS m/z (M+H) 291.0 found, 291.1 required. 1H NMR (2-4) (500 MHz, CDCl3): δ 7.77 (d, J=2.3 Hz, 1H); 7.73 (s, 1H); 6.47-6.43 (m, 1H); 6.17-6.14 (m, 1H); 5.87 (s, 1H); 5.41 (d, J=6.0 Hz, 1H); 5.00 (s, 2H); 4.69 (d, J=6.1 Hz, 1H); 1.55 (s, 3H); 1.38 (s, 3H). LRMS m/z (M+H) 291.0 found, 291.1 required.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][C:13]([NH:14][C:5]2[C:4]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH3:9])=[CH:11][CH:12]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: Oc1cccnc1O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours; and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(p-tolylamino)-2,3-pyridindione in a red powder. The yield was 32%-54%.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[O:1]([CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), phenol (525 mg, 5.6 mmol), triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then the mixture was extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-phenoxyethyl)benzoate (700 mg, 54%). 1H NMR (300 MHz, d6-DMSO): δ 8.02-7.98 (m, 2H), 7.46-7.43 (m, 2H), 7.23-7.16 (m, 2H), 6.91-6.80 (m, 3H), 5.36 (q, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])=[CH:10][CH:11]=2)[O:6][C:5](=[O:26])[CH:4]=1.Cl.[OH-:28].[Na+]>>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:26])=[O:28])=[CH:2][O:6][C:7]=2[CH:8]=1)(=[O:15])=[O:16])([O-:25])=[O:24]
Reactant: [OH-]
Reactant: O=c1cc(CCl)c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2o1
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-[4-(chloromethyl)-2-oxo-2H-chromen-7-yl]-2-nitrobenzenesulfonamide (14.3 g, 36.2 mmol) and 1 M aqueous sodium hydroxide solution (120 mL) was stirred at room temperature for 24 hr. The reaction mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (13.6 g, quant.) as pale-brown crystals.