Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.B.O1CCCC1>O1CCCC1.O.C(OCC)(=O)C>[OH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]2=[O:12])=[CH:18][CH:17]=1)[CH3:23]
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)O)cc1)C2
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)CO)cc1)C2
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A mixture of 2-(4-(6-methoxy-1-oxoisoindolin-2-yl)phenyl)propanoic acid (0.102 g, 0.33 mmol) and borane-tetrahydrofuran complex (0.83 mL, 1 M in tetrahydrofuran, 0.83 mmol) in tetrahydrofuran (2 mL) at 0° C. was stirred for 3 h. After this time, the reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and the mixture stirred vigorously for 18 h at room temperature. The aqueous layer was separated and extracted with ethyl acetate (25 mL), and the combined organic layers dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an off-white solid. Purification by flash chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 2-(4-(1-hydroxypropan-2-yl)phenyl)-6-methoxyisoindolin-1-one (0.081 g, 84%) as a white solid: mp 135-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J=8.6, 19 Hz, 2H), 7.41-7.39 (m, 2H), 7.31 (d, J=8.6 Hz, 2H), 7.16 (dd, J=8.4, 2.4 Hz, 1H), 4.79 (s, 2H), 3.89 (s, 3H), 3.72 (d, J=6.8 Hz, 2H), 2.98 (q, J=6.9 Hz, 1H), 1.30 (d, J=7.0 Hz, 3H); ESI MS m/z 298 [M+H]+.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C(Br)=C.[CH3:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH:6]=[CH2:7])[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: CCN(CC)CC
Reactant: CC1CCc2ccccc2C1=O
Agent: [Pd+2]
Agent: C=CBr
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C=CC1(C)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 891.3 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was purged with argon. The septum was removed, and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol %) and (−)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (13.6 mg, 0.028 mmol 5.5 mol %). The tube was capped with the septum, purged with argon, and toluene (2 mL) and triethylamine (5 mg, 0.05 mmol) were added through the septum. The mixture was stirred at room temperature for 3 min, then vinyl bromide (1.0 mL 1.0 mmol) and 2-methyl-1-tetralone (81 mg, 0.5 mmol) were added through the septum. The septum was removed and sodium t-butoxide (96 mg, 1.0 mmol) was added. The tube was capped with the septum and purged with argon. Additional toluene (4 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 83 mg (88%) of title compound. The ee was 9 determined to be 79% by chiral HPLC analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:4]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:25][OH:26])=[O:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.ClCCl>[C:27]([O:26][CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18]([C@@:4]1([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])=[O:19])(=[O:29])[CH3:28]
Reactant: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 171B (54 mg, 0.15 mmol) in anhydrous pyridine (0.5 mL) was added acetic anhydride (50 μL, 0.53 mmol). The resulting mixture was stirred under a N2 atmosphere at r.t. for 16 h, diluted with dichloromethane (10 mL), and extracted with 0.2 N HCl (2× 10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 25-50% ethyl acetate in hexane. The title compound was obtained as a colorless solid (50 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 0.51 (m, 1H), 0.71 (d, J=6.62 Hz, 3H), 0.77 (d, J=6.62 Hz, 3H), 0.94 (m, 2H), 1.39 (m, 2H), 1-64 (m, 3H), 2.04 (m, 1H), 2.04 (s, 3H), 2.26 (m, 1H), 2.49 (m, 1H), 3.16 (m, 1H), 3.47 (m, 1H), 3.59 (s, 3H), 4.11 (m, 1H), 4.25 (m, 1H), 4.41 (m, 1H), 4.97 (m, 1H), 7.14 (m, 4H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:23]=[CH:22]1
Reactant: Oc1ccncc1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccc(=O)cc2)cc1)c1ccccc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.43 (br s, 3H), 4.92 (s, 2H), 6.43 (d, 2H), 7.17 (br s, 4H), 7.22–7.42 (m, 9H), HPLC-MS: m/z=335.0 (M+1); Rt=2.55 min.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH2:15][CH2:16][OH:17])[CH:5]=1)([O-:3])=[O:2].[CH3:18]N>C(O)C.C(N)=O>[CH3:18][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH2:15][CH2:16][OH:17])=[C:7]([OH:13])[CH:8]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: NC=O
Product: CNc1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture consisting of 0.115 mol (28.2 g) of 4,5-dinitro-2-(β-hydroxyethoxy)phenol, prepared in Example 3, in 300 ml of a 33% strength solution of methylamine in absolute ethanol and 100 ml of formamide is heated to 95° C. for 6 hours in an autoclave (pressure 5-6 kg/cm2) After the reaction medium has been cooled, the expected product crystallizes. It is recrystalized from formamide. It melts at 210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution (4 mL) of the compound (180 mg, 0.45 mmol) obtained in Example 37a in ethanol was added 2N aqueous sodium hydroxide solution (1.6 mL, 3.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (95 mg, 57%) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15](O)=[O:16])[CH3:13]>>[CH:1]1([NH:8][C:9]2[S:10][C:14]([CH2:18][CH3:19])([CH2:12][CH3:13])[C:15](=[O:16])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(CC)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: CCC1(CC)SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and 2-ethylbutyric acid according to Method J and D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Two portions of 4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) were dissolved in CH2Cl2 (7.0 mL) in reaction flasks. Aniline (757 mg, 8.13 mmol) was added drop-wise at room temperature, followed by slow additions of pyridine (2.0 mL). After 16 h of continued stirring, the reaction mixtures were diluted with ethyl acetate (50 mL) and washed with 1 M HCl (3×50 mL). The organic phases were dried (MgSO4) and evaporated to brown solids, which upon re-crystallization from ethanol/water gave off-white solid of the product 2.04 g (96%): 1H NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H), 7.80 (dd, 1H), 7.61 (d, 1H), 7.30 (t, 2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.79 (bs, 1H); MS (CI) 310.8 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][N:9]([C:13](=[O:22])[CH2:14][O:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:8][CH:7]1[C:23]([OH:25])=[O:24].[N:31]1C=NC=N[CH:32]=1.CC(O)=O>CCO>[NH2:30][C:29]1[C:28]2[C:2](=[CH:3][C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH2:10][N:9]([C:13](=[O:22])[CH2:14][O:15][C:16]4[S:17][C:18]([Cl:21])=[CH:19][CH:20]=4)[CH2:8][CH:7]3[C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[N:1]=[CH:32][N:31]=1
Reactant: N#Cc1ccc(CN2C(=O)CN(C(=O)COc3ccc(Cl)s3)CC2C(=O)O)cc1N
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2cc(CN3C(=O)CN(C(=O)COc4ccc(Cl)s4)CC3C(=O)O)ccc12
Yield: 105.1 %

Procedure:
A solution containing (+/−)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid (20 mg, 0.03 mmol), 1,3,5-triazine (28 mg, 0.34 mmol), and glacial HOAc (20 mg, 0.34 mmol) in absolute EtOH (6 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 15 mg (75%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.75-4.38 (m, 5H), 4.67 (d, J=14.8 Hz, 1H), 4.79 (d, J=15.3 Hz, 1H), 4.95 (m, 1H), 5.09 (br d, J=16.0 Hz, 1H), 6.18 (m, 1H), 6.71 (m, 1H), 7.64 (m, 2H), 8.31 (d, J=8.5 Hz, 1H), 8.75 (s, 1H), 9.64 (br s, 2H) ppm; MS (ISP loop): m/z 476 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:31])=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([CH3:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:31])=[CH:26][CH:25]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C1(C(N)=O)CC1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A40 (0.300 g, 0.950 mmol), tert-butyl (1-(4-aminophenyl)ethyl)carbamate (0.449 g, 1.90 mmol), Pd(OAc)2 (0.004 g, 0.019 mmol), xantphos (0.022 g, 0.038 mmol) and Cs2CO3 (0.929 g, 2.85 mmol) in dioxane (15 mL) was bubbled with N2 for 10 minutes and then stirred in the microwave at 120° C. for 20 minutes. The volatiles were removed in vacuo and the residue was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A47 as a white solid (0.110 g, 22%). LCMS-D: rt 3.52 min; m/z 516 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(Br)c(=O)n(C2CCCC2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COC(=O)c1cc(N2CCCC2)c(=O)n(C2CCCC2)c1
Temperature: 95 °C

Procedure:
A mixture of methyl 5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg, 0.33 mmol), pyrrolidine (33 uL, 0.40 mmol), cesium carbonate (150 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (0) (3 mg, 0.0033 mmol), rac-2-2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (3.1 mg, 0.005 mmol) was purged with nitrogen for 30 min, followed by the addition of anhydrous toluene (1.5 mL). The resulting light-brown solution was heated to 95° C. for 17. The mixture was brought to room temperature and partitioned between ethyl acetate and saturated NH4Cl. The organic phase was separated, washed with saturated NH4Cl, brine, dried over MgSO4 and chromatographed on silica gel using 3:1 hexanes:ethyl acetate to afford the title compound as a yellow oil. MS m/z: 291 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:32]C(=O)OC(C)(C)C)([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:40].C(OC(C)C)(C)C>ClCCl.C(OCC)(=O)C>[ClH:40].[NH2:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:24][CH:25]=1)([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-n2c(-c3cccnc3N)nc3ccc(-c4ccccc4)nc32)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(N)c1ccc(-n2c(-c3cccnc3N)nc3ccc(-c4ccccc4)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}-1-methylethyl)carbamate (27 mg) in dichloromethane (1 mL) was added a solution of hydrogen chloride in ethyl acetate (80 ul). The reaction was allowed to stir at room temperature for 1 h. Upon completion of the reaction, diisopropylether was added to the suspension and the solid was filtered to give the product (19 mg, 71%). 400 M Hz 1H-NMR (DMSO-d6) δ: 8.90-8.70 (m, 3H), 8.37 (d, J=8.3 Hz, 2H), 8.15 (dd, J=6.0 Hz and 1.8 Hz, 1H), 8.08-8.03 (m, 3H), 7.86 (dd, J=7.3 Hz and 1.4 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.52-7.47 (m, 2H), 7.46-7.41 (m, 1H), 6.89 (dd, J=7.3 Hz and 6.4 Hz, 1H), 1.70 (s, 6H); LCMS: 421 [M+H].
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=2)=[CH:28][CH:29]=1
Reactant: Cc1cncc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCOC=O)c(=O)n3C)c1
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cncc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (56 mg, 0.113 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (9.5 mg, 0.226 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11 mg, 21% yield) as a white solid. 1H NMR (CD3OD) δ: 8.43 (s, 1H), 8.13-7.95 (m, 2H), 7.22-7.05 (m, 4H), 6.94 (s, 1H), 4.81 (s, 2H), 4.18 (t, J=7.1 Hz, 2H), 3.72 (s, 3H), 3.65 (t, J=6.3 Hz, 2H), 2.24 (s, 3H), 1.98-1.84 (m, 2H). LCMS: MH+ 467 and TR=2.631 min.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:24]=[CH:23][S:22][C:13]=4[C:14](=[O:21])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)C(C)C)(C)C>C(Cl)Cl.C1COCC1>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:21])[C:13]3[S:22][CH:23]=[CH:24][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([CH:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(NS(C)(=O)=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1.5 h
Yield: 19.5 %

Procedure:
A solution of 9-[4-(1-aminoethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (30 mg, 0.089 mmol) and methanesulfonyl chloride (9.0 μL, 0.11 mmol) in 2:1 methylene chloride/THF (3 mL) was stirred at room temperature for 10 min followed by the addition of N,N-diisopropylethylamine (19 μL, 0.11 mmol). The reaction mixture was stirred for 1.5 h, concentrated and purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (7.2 mg, 20%) as an amorphous brown solid: 1H NMR (500 MHz, CD3OD) δ 7.57-7.56 (m, 2H), 7.53 (d, J=5.4 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.32-7.30 (m, 2H), 7.16 (d, J=8.9 Hz, 1H), 6.02 (d, J=5.4 Hz, 1H), 4.71 (q, J=4.6 Hz, 1H), 2.82 (s, 3H), 1.62 (d, J=7.0 Hz, 3H); ESI MS m/z 415 [C20H18N2O4S2+H]+; HPLC >99%, tR=10.18 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:23])[CH:3]=1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].CCN(CC)CC>CN(C=O)C.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:24](=[O:27])[CH:25]=[CH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:23])[CH:3]=1)[CH3:30]
Reactant: C=CC(=O)OCC
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of 4-[(4-bromo-2-fluoro-phenyl)-cycloheptylidene-methyl]-phenol (175) (1.0 g, 2.66 mmol) in DMF (27 mL) was added ethyl acrylate (2.9 mL, 26.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.187 g, 0.266 mmol) and Et3N (2.2 mL, 15.99 mmol). The reaction mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and EtOAc (20 mL). The aqueous mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was loaded onto silica gel and purified by flash chromatography with a hexanes:EtOAc gradient (100:0 to 90:10) to give 0.85 g (81%) of the title compound 176 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 1.22 (t, J=7.1 Hz, 3H), 1.48-1.51 (m, 8H), 2.07-2.10 (m, 2H), 2.25 (s, 2H), 4.13-4.18 (m, 2H), 6.61-6.66 (m, 3H), 6.92 (d, J=8.6 Hz, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.47 (d, J=6.6 Hz, 1H), 7.56-7.60 (m, 2H), 9.32 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:23]=2[N:22]=1)[CH2:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[S:15][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:49])[C:42]([OH:44])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.ClCl>CN(C)C=O>[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([C@@H:9]([NH:8][C:42](=[O:44])[C:41]3[CH:45]=[CH:46][C:47]([C:48]([N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:49])=[C:39]([CH3:38])[CH:40]=3)[CH2:10][CH2:11][C:12]3[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[S:15][CH:16]=3)=[N:22][C:23]=2[CH:29]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(C)Nc1nc(CC[C@H](NC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CCc2csc(NC(C)C)n2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 45 %

Procedure:
Prepared analogously to Example 17 from N-(tert-butoxycarbonyl)-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(2-isopropylaminothiazol-4-yl)propylamine] and trifluoroacetic acid and subsequent reaction with 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, and diisopropylamine in dimethylformamide. Yield: 45%; C29H33ClN6O2 (565.139); mass spectrum: (M+H)+=565/567 (chlorine isotope).