Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([O-:18])=[O:17])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Li+].[OH-].O>C1COCC1.CO>[N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1ccc(C(=O)[O-])cc1NC(=O)c1cnc2ccccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) (5.43 g, 17.6 mmol) in THF (225 ml) and MeOH (150 mL) was added LiOH 3 M (17.5 mL) and water (50 mL). The reaction was stirred at room temperature for 12 hours then reduced in volume on roto-vap to remove THF and MeOH. The mixture was diluted with water (75 mL) and neutralized with HCl (17.5 mL of a 3M solution). The resulting precipitate was filtered, washed with water and dried under vacuum to afford 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoic acid (4) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.0 (s, 1H), 9.45 (dt, J=6.8, 1.2 Hz, 1H), 8.58 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.35 (s, 3H). MS m/z 296.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@@H:7]([C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=O)=[CH:4][C:3]=1[CH3:26].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][C:29]=1[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[C:3]([CH3:26])[CH:4]=2)[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])=[CH:30][C:29]=1[CH3:36]
Reactant: Cc1cc(O[C@H](CCCC=O)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Reactant: Cc1cc(CN)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(CNCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-(4-fluoro-3-methylphenoxy)-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-6-oxohexanal (70 mg, 0.19 mmol) in 3 mL DCE was added 4-Fluoro-3-methyl-benzylamine (32 mg, 0.23 mmol) followed by NaBH(OAc)3 (56 mg, 0.26 mmol) and AcOH (13.8 mg, 0.23 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])([O-])=O>CO.[OH-].[Na+].[Ni]>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12]
Reactant: CSCC[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NCc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
780 gm of N-(2-nitro-benzyl)-methionine were dissolved in a mixture of 5 liters of methanol and 280 cc of aqueous 30% sodium hydroxide in a tightly sealable vessel equipped with an effective stirrer. 100 gm of Raney nickel were added to the solution, the vessel was sealed, and the contents were hydrogenated at a pressure of about 70 gm/cm2, accompanied by stirring. The internal temperature rose gradually to about 60° C. and fell again when the hydrogenation reaction had gone to completion. The reaction mixture was then cooled to room temperature, the Raney nickel was filtered off, and the methanolic filtrate was neutralized with acetic acid, whereupon the hydrogenated product slowly precipitated out. The reaction mixture was allowed to stand overnight. The precipitated substance was centrifuged off, washed with a little methanol, and dried at 60° C. in a ventilated drying chamber, yielding 570 gm (80% of theory) of the creme-colored crystalline compound of the formula ##STR10## which had a melting point of 217° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:17](O)[CH2:18][OH:19]>>[ClH:1].[OH:19][CH2:18][CH2:17][O:13][C:12](=[O:14])[C@H:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1)[NH2:11]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: OCCO
Agent: Cl
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
Dry hydrogen chloride (68.3 g) was dissolved in ethylene glycol (994 mL) at <20° C. and then solid 4-nitro-(S)-phenylalanine (198.7 g) added with stirring. The mixture was heated to 80-85° C. and held at this temperature for 2 h. After a LC completion check, the preparation was allowed to drift to 60° C. and seeded with authentic product. Once crystallisation had initiated, the resulting suspension was cooled further to 20° C. and stirred out overnight. The 4-nitro(S)-phenylalanine hydroxyethyl ester hydrochloride was collected by filtration, washed in situ with dimethoxyethane (795 mL), and then dried in vacuo at 40-45° C. to constant weight (white powder m.p. 195-197° C., 187.0 g, 73.9% yield). 1H NMR (D6-DMSO): δ3.27 (2H, ddd); 3.42 (2H, m); 4.01 (2H, m); 4.27 (1H, t); 4.88 (1H, b,s); 7.52 (2H, d); 8.11 (2H, d); 8.76 (3H, b,s) ppm. Mass Spectrum: ESI+ (m/z+1) 255.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CO.ClCCl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:24]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Oc1cccnc1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1cccnc1
Yield: 14 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxypyridine (12 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 9 mg (14%) of the titled compound. ESI-MS m/z 391 (M+Na+), 367 (M−H−).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1>C(O)C>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])nc1
Solvent: CCO
Product: CN(C)CCN(C)c1ccc(N)nc1
Reaction time: 3 h
Yield: 100.3 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 1.00 g dry weight) and a solution of 270a (2.20 g, 9.80 mmol) in ethanol (150 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a quantitative yield of 270b (1.91 g) as a purple oil: 1H NMR (500 MHz, CDCl3) d 7.67 (d, 1H, J=2.9 Hz), 7.05 (dd, 1H, J=8.5, 2.9 Hz), 6.48 (dd, 1H, J=8.9, 0.5 Hz), 4.04 (br s, 2H), 3.28 (t, 2H, J=7.1 Hz), 2.84 (s, 3H), 2.43 (t, 2H, J=7.4 Hz), 2.26 (s, 6H); MS (ESI+) m/z 195.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH2:34]Br>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:13][N:12]([CH2:34][C:33]3[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
Combine 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy) -ethyl]-pyrrolidine (10 mmol), K2CO3 (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10 mmol) in THF/H2O (4/1, 200 mL). Heat to reflux and stir for 16 h. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with H2O. Separate the layers, dry the organic layer over MgSO4, filter, and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([OH:18])=O)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:18])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid was coupled with 2,2,3,3,3-pentafluoropropylamine in analogy to the procedure described for RJR 7 to yield (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([N:29]([CH3:59])[C:30]([C:32]1[C:33]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[N:34][N:35]2[C:40]([F:41])=[CH:39][C:38]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:45](O)=[O:46])=[CH:37][C:36]=12)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:41][C:40]1[N:35]2[N:34]=[C:33]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[C:32]([C:30]([N:29]([CH3:59])[C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:31])=[C:36]2[CH:37]=[C:38]([C:42]2[CH:43]=[C:44]([C:45](=[O:46])[NH:12][C:9]3([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[CH2:11][CH2:10]3)[CH:48]=[CH:49][C:50]=2[CH3:51])[CH:39]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.011 g, 0.054 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.054 mmol) and DMF (0.36 mL) was added HATU (0.041 g, 0.11 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.428 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 638 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1[C:25]1([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]1)C(=O)N2.ClCC1OC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:34]1[CH:33]=[CH:25][CH:36]=[C:35]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: ClCc1ccco1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccco2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound (40%) as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8, 123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:16])=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C2Cc3ccccc3O2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3Cc4ccccc4O3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of 4-(2,3-dihydrobenzofuran-2-yl)benzoic acid (0.02 g, 0.08 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.04 g, 0.2 mmol) and N-hydroxybenzotriazole (0.02 g, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.10 g, 1.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.03 g, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water. The organic phase was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product as a white solid 4-(2,3-dihydrobenzofuran-2-yl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-51) (0.02 g, 66%). LRMS (M+H+) m/z: calcd 374.16. found 374. 1H NMR (300 MHz, CD3OD): δ 7.80-7.77 (m, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.18-7.12 (m, 2H), 6.87-7.80 (m, 2H), 6.09 (s, 1H), 5.79 (t, J=9.0 Hz, 1H), 4.49 (s, 2H), 3.73-3.64 (m, 1H), 3.14-3.06 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[OH-].[Na+]>CO.O>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[N:10]=[CH:9][CH:8]=[C:7]2[NH:6][C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=1[F:25])([OH:19])=[O:18]
Reactant: COC(=O)c1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C(=O)O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-methoxycarbonylquinoline (1.79 g, 4.9 mmol), (prepared as described in Example 55), and sodium hydroxide (0.6 g, 15 mmol) in methanol (75 ml) and water (5 ml) was heated at 70° C. for 4 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The solid residue was suspended in water and acetic acid was added to adjust the aqueous suspension to pH5. The mixture was stirred for 15 minutes and the solid product was collected by filtration, washed with water and then acetone and finally ether, and dried to give 6-carboxy-4-(4-chloro-2-fluoroanilino)-7-methoxyquinoline (1.55 g, 90%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[N:21]=[C:22]([C:26]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:27]=2)[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cccc(OCc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(OCc3ccccc3)n2)sc2ccccc12
Yield: 25.3 %

Procedure:
A mixture of methyl thiosalicylate (0.40 g, 2.4 mmol), 2-benzyloxy-6-cyanopyridine (0.50 g, 2.4 mmol), triethylamine (0.50 ml, 3.6 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.21 g, 26%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[N:42]=[CH:41][N:40]=[C:39]3[C:35]=2[N:36]=[CH:37][N:38]3[CH2:43][C:44](O)=[O:45])=[O:32])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:38]1[CH:37]=[N:36][C:35]2[C:39]1=[N:40][CH:41]=[N:42][C:34]=2[NH:33][C:31]([O:30][CH2:29][C:28]1[CH:47]=[CH:48][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:32])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)cc3)ncnc21
Yield: 102.5 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (172 mg, 0.5 mmol), [6-N-(4-methoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (179 mg, 0.5 mmol), and HBTU (190 mg, 0.5 mmol) in DMF (2 ml) was added diisopropylethylamine (0.09 ml, 0.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 2 h at the same temperature and 1N HCl was added to the reaction mixture. The resulting precipitate product was filtered off, washed with water, and dried in vacuo to give the title compound as a white solid (0.35 g, 97%). 1H NMR (500 MHz; DMSO-d6) δ 8.97 (t, 0.6H) 8.76 (t, 0.4H) 8.64 (s, 0.4H) 8.60 (s, 0.6H) 8.53 (d, 1H) 8.28 (m, 1H) 8.17 (d, 1H) 7.66 (m, 2H) 7.40 (d, 2H) 6.95 (d, 2H) 5.41 (s, 1.2H), 5.20 (s, 0.8H) 5.18 (s, 2H) 4.46 (s, 0.8H) 4.18 (q, 0.8H) 4.08 (s, 1.2H) 4.03 (q, 1.2H) 3.75 (s, 3H) 3.70 (q, 1.2H) 3.48 (q, 1.2H) 3.42 (t, 0.8H) 3.22 (q, 0.8H) 1.24 (t, 1.2H) 1.13 (t, 1.8H)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:18]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
A solution of freshly prepared 4-hydroxybenzoic acid (635 mg; 4.6 mmol) and BOP (1.7 g; 5.06 mmol) in DMF (20 mL) was added dropwise and at room temperature to a solution of PEI (1 g, 23.2 mmol) in DMF (50 mL). After 2 hours under stirring, the DMF was removed by evaporation under reduced pressure. The crude product was taken in water, dissolved by addition of aqueous sodium hydroxide solution 1M (pH 11) and subjected to dialysis against water (1 L, 2 changes over 24 h). Lyophilization provided 4-hydroxybenzamide-PEI (0.7 g) at a modification degree of 28%. 1H NMR (D2O) δppm: 2.6 (bm, 2.9H, —NHCH2CH2NH—), 3.22 (m, 0.55H, Phe-CONHCH2CH2NH—), 3.35 (m, 0.55H, Phe-CONHCH2CH2NH) 6.57 (d, J=7.3 Hz, 0.55H, CHaro), 6.97 (m, 0.55H, CHaro).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>O.[Cu]Cl>[NH2:6][C:3]1[CH:4]=[CH:5][N:1]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:2]=1
Reactant: Brc1cccnc1
Reactant: Nc1cc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccn(-c2cccnc2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A 4-neck round bottomed flask (500 mL) was charged with copper(I) chloride (2.51 g, 25.3 mmol), 1H-pyrazol-3-amine (15.8 g, 190 mmol), potassium carbonate (35.0 g, 253 mmol), and N,N-dimethylformamide (100 mL). The mixture was stirred under nitrogen for 10 minutes and 3-bromopyridine (12.2 mL, 127 mmol) was added. The mixture was heated at 110° C. for 18 hours, at which point HPLC analysis indicated that ˜15.5% 3-bromopyridine remained. The reaction was allowed to cool to 20° C. and concentrated to give a brown residue. Water (200 mL) was added and the resulting suspension was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and dried to afford a pale green solid. The solid was suspended in water (200 mL) and the resulting suspension was heated at 90° C. for 2 hours and was filtered hot through a Celite® pad. The pad was rinsed with hot water (50 mL). The combined filtrates were allowed to cool to 20° C. to afford a yellow suspension, which was stirred at 20° C. for 2 hours and filtered. The solid was rinsed with water (2×50 mL) and air dried to afford the desired product as a light yellow crystalline solid (11.6 g, 57%).