Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][S:34](Cl)(=[O:36])=[O:35])([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:34]([CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])(=[O:35])=[O:36])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3[N+](=O)[O-])CC2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A light brown solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 560 mg, 1.78 mmol) and (2-nitrophenyl)methanesulfonyl chloride (837 mg, 3.55 mmol) in THF (30 mL) was cooled to 0° C. under nitrogen and then N,N-diisopropylethylamine (930 μL, 5.34 mmol) was added. The resulting light brown solution was stirred for 2 hours at 0° C. temperature and then allowed to warm to room temperature and stirred for 36 hours. The reaction mixture was diluted with water and brine and the organic compound was extracted into ethyl acetate (2×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered, and concentrated. The crude product was purified using flash chromatography (120 g ISCO column eluting with 0-60% ethyl acetate/hexanes) to give {6-fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (645 mg, 71%) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.07-8.1 (m, 1H), 7.85 (br. s, 1H), 7.55 (dd, J=8.8, 6.3 Hz, 1H), 7.67-7.72 (m, 2H), 7.56-7.64 (m, 2H), 7.16-7.24 (m, 1H), 4.83 (s, 2H), 3.89 (d, J=10.0 Hz, 2H), 3.82 (br. s, 2H), 3.72 (s, 3H), 3.43-3.63 (m, 1H), 2.90 (t, J=11.5 Hz, 2H), 2.32-2.71 (m, 5H), 1.77 (d, J=13.8 Hz, 2H). MS cald. for C26H27FN2O6S [(M+H)+] 514, obsd. 515.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=3[CH3:26])[CH:13]=[CH:12][C:11]=2[O:27][CH3:28])=[CH:5][N:4]=1.[C:29]([NH:32][CH2:33][C:34]([OH:36])=[O:35])(=O)[CH3:30].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:30][C:29]1[O:36][C:34](=[O:35])[C:33](=[CH:24][C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]3[CH:13]=[CH:12][C:11]([O:27][CH3:28])=[C:10]([CH2:9][C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:15]=3)=[C:18]([CH3:26])[CH:19]=2)[N:32]=1
Reactant: COc1ccc(Cc2cc(Oc3c(C)cc(C=O)cc3C)ccc2OC)cn1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cc2cc(Oc3c(C)cc(C=C4N=C(C)OC4=O)cc3C)ccc2OC)cn1
Reaction time: 24 h
Yield: 62.8 %

Procedure:
2-Methoxy-5-(2-methoxy-5-(2,6-dimethyl-4-formylphenoxy)benzyl) -pyridine (10.84 g), N-acetylglycine (5.38 g), sodium acetate (3.77 g) and acetic anhydride (70 ml) were stirred at 100±5°, (oil bath temperature) for 24 hours. The solution was cooled and evaporated to leave a brown gum which was triturated with water, then with methanol to afford 2-methyl-4-(3,5-dimethyl-4-(4-methoxy -3-(6-methoxy-3-pyridylmethyl)-phenoxy)-benzal)-5-oxazolone as a yellow solid (8.27 g, 64%), m.p. 164-165°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH2:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:28][C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(NCc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (57 mg, 0.319 mmol) was reacted with the product from Example 44c (102 mg, 0.319 mmol) for 72 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (169 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.74 (s, 3H) 4.30 (s, 2H) 6.15 (d, J=6.99 Hz, 1H) 6.52 (d, J=8.46 Hz, 1H) 6.56-7.39 (m, 11H) 7.75 (d, J=8.46 Hz, 1H) 8.28 (d, J=7.36 Hz, 1H) 9.50 (br s, 1H) 10.85 (br s, 1H) 14.25 (br s, 1H); MS (ESI+) m/z 465 (M+H−TFA)+; (ESI−) m/z 463 (M−H−TFA)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:27])[N:3]=1.[F:28][C:29]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:4]1[N:3]=[C:2]([C:35]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([F:28])[CH:36]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: COc1cccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
A mixture of 4-chloro-6-(2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-2-pyrimidinamine (770 mg, 1.991 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (590 mg, 2.389 mmol), Na2CO3 (464 mg, 4.38 mmol) and Pd(PPh3)4 (138 mg, 0.119 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washing with EtOAc (100 mL), and concentrated to afford the crude title compounde (1.0 g) as a grey oil. This material was combined with another sample of the title compound (100 mg). The combined material was purified by silica gel chromatography, eluting with EtOAc in PE from 50% to 80% to afford the title compound (760 mg) as a brown solid. LC-MS (ES) m/z=472 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]=[S:26]1(=[O:41])[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:34][CH2:33][N:32]([CH:29]4[CH2:30][CH2:31][S:26](=[O:41])(=[O:25])[CH2:27][CH2:28]4)[CH2:37][CH2:36]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C2CCS(=O)(=O)CC2)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CCS(=O)(=O)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 592.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (320 mg, 1.16 mmol) [prepared according to the procedure of Example 168], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (318 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (9.5 mL). DIEA (840 μl, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (106 mg, 0.16 mmol, 17%): LC-MS (ES) m/z=557 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CN(C)C=O>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3ccc(Cl)cc3C2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccc(Cl)cc3C2C)c1C
Product: Cl
Yield: 61 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-4-(1-methyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.31 mmol) prepared in Step 1 above, dimethylformamide (5 ml), and 4-fluoroaniline (0.07 ml, 0.74mmol) to afford 82 mg (61.3%) of the titled compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0 mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g, 53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and crystals were filtered with hexane. The filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (300 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (7.5 g, 39%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.Cl>C1COCC1.C(O)C>[C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCCc2ccccc2)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](OCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 9 g of trans-2-(4-phenylethyloxy-cyclohexyl)-isoindole-1,3-dione in 60 mL of THF and 150 mL of ethanol was added 3.75 mL of hydrazine hydrate and the mixture heated to reflux for 4 h, then 80 mL of 6N HCl was added and the reflux was continued for 1 h. The cooled mixture was concentrated under reduced pressure to remove ethanol and filtered. The filter pad was washed with 2×50 mL of dilute HCl and the combined filtrates basified to pH 10 with 20% sodium hydroxide and extracted with 3×150 mL portions of chloroform. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Further drying under vacuum gave 6 g of product as an oil. MS (m+1)=220.2; 1H NMR (400 MHz, CDCl3) 7.3-7.1 (m, 5H), 3.7 (t 2H), 3.2 (m, 1H), 2.9 (t, 2H), 2.7 (m, 1H), 2.0 (d, 2H), 1.85 (d, 2H), 1.4 (br s, 2H), 1.3 (dd, 2H), 1.15 (dd, 2H).
Reaction SMILES: [ClH:1].[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[O:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:10][CH2:11][CH:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8]2)=[O:24])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)N1CCC(N2CCCC2)C1
Reaction time: 8 h

Procedure:
A stirred mixture of the HCl salt of 3-(pyrrolidino)pyrrolidine (0.44 g, 2.1 mmol) and 4-phenoxy benzoic acid (0.34 g, 1.6 mmol) in CH2Cl2 is treated with 0.85 mL of triethylamine at room temperature. The reaction mixture is treated with solid benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.4 mmol), stirred overnight under nitrogen, diluted with CH2Cl2, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed and treated with HCl in ether to afford the title compound as a white solid, identified by NMR and MS analyses.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[F:24][C:25]([F:30])([F:29])[C@H:26]([NH2:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(#N)C.[OH2:42]>>[C:26]([OH:21])([C:25]([F:30])([F:29])[F:24])=[O:42].[CH3:22][C:3]1[C:2]([NH:28][C@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H](C)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 100 °C
Yield: 0.1 %
Yield: 10 %

Procedure:
Prepared similarly to that described in Example 254 using 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 254c; 47 mg, 0.150 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (44.9 mg, 0.301 mmol, SynQuest Laboratories, Alachua, Fla.), Pd(tBu3P)2 (Strem, Newburyport, Mass.; 7.68 mg, 0.015 mmol), and K3PO4 (128 mg, 0.601 mmol), heating at 100° C. for 18 h. Purification by silica gel (100% DCM to 4% 2 M NH3 in MeOH/DCM) then by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided (R)-2-(2-methyl-3-((1,1,1-trifluoropropan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (10% yield). MS (ESI, pos. ion) m/z: 390.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.61 (br. s., 3H) 2.66 (s, 3H) 2.96 (t, J=6.85 Hz, 2H) 3.66 (td, J=6.90, 2.45 Hz, 2H) 4.81 (s, 1H) 4.91 (dq, J=14.04, 6.93 Hz, 1H) 5.29 (br. s., 1H) 7.12 (d, J=2.15 Hz, 1H) 7.48 (t, J=7.82 Hz, 1H) 7.73 (d, J=7.04 Hz, 1H) 7.95 (dd, J=7.63, 1.17 Hz 1H) 11.59 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −76.30 (3F, s).
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.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>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)c2ccccc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
2-methyl-4-(1-phenylethyl)benzoic acid (150 mg, 0.6 mmol) was dissolved in 20 mL dichloromethane, and then N-hydroxybenzotriazole (0.9 mmol, 100 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol, 200 mg), triethylamine (10.48 mmol, 3 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.6 mmol, 90 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (30 mL), extracted with dichloromethane (40 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (150 mg, 90%). 1H NMR (300 MHz, CD3OD): δ 7.25-7.05 (m, 8H), 6.08 (s, 1H), 4.44 (s, 2H), 4.09 (m, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H) 1.59 (d, J=8.4 Hz, 3H); LRMS (M+H+) m/z: calcd 374.20. found 374.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.C(Cl)[Cl:31].CO>Cl.O1CCOCC1>[ClH:31].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reaction time: 48 h
Yield: 98 %

Procedure:
A solution of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate (1.17 g; 3.00 mmol; 1.0 eq.) in HCl solution in 1,4-dioxane (7.5 mL, 4N) was stirred at RT. After 48 h, the reaction mixture was concentrated to dryness affording a sticky solid, which was sonicated in a 1:1 mixture of DCM/MeOH. The suspension obtained was concentrated to dryness to afford the title compound as a beige solid (967 mg, 98%). HPLC (Condition A): Rt 2.08 min (purity 95.3%). MS (ESI+): 291.1, MS (ESI−): 289.2. Purification by preparative HPLC of 50 mg of this crude by afforded a pure sample (35 mg): 1H NMR (300 Mz, DMSO-d6) δ: 13.40 (brs, 1H), 9.33 (s, 1H), 8.36 (dt, J=8.2 Hz, J=1.0 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.62 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 4.02 (s, 2H). HPLC (Condition A): Rt 2.06 min (purity 97.5%). MS (ESI+): 291.1, MS (ESI−): 289.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](=O)([O-])O.[Na+].Br[CH2:16][CH2:17][C:18]([O:20]C)=[O:19].O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:10][N:5]([C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[CH3:9])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C([O-])O
Reactant: Cc1c(N)cccc1Cl
Reactant: COC(=O)CCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(Cl)cccc1N(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
1.00 g of 3-chloro-2-methylaniline was dissolved in 10 mL of hexamethylphosphoramide, and 1.80 g of sodium hydrogen carbonate and 1.19 g of methyl 3-bromopropionate sequentially were added thereto, followed by stirring at room temperature for 4 hours. To the reaction liquid was added water, followed by extraction with diisopropyl ether. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 85:25) to obtain 0.92 g of methyl N-(3-chloro-2-methylphenyl)-β-alanine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-Iodophenol (2.2 g, 10 mmol) was dissolved in N,N-dimethylformamide (30 mL) under N2, and sodium hydride (0.48 g, 60% dispersion in mineral oil, 12 mmol) was added in portions. 1-(3-Chloropropyl)pyrrolidine (1.77 g, 12 mmol) and sodium iodide (1.8 g, 12 mmol) were added, and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was washed with 1 N HCl (2×). The acidic extracts were made basic with 2 N NaOH, then were extracted with ethyl acetate (2×). All ethyl acetate extracts were combined, dried over MgSO4 and concentrated to give a yellow oil, 2.98 g (90% crude yield). LC-MS (C13H18INO calc'd 331) m/z 332 (M+H).