Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 3-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (0.150 mg, 0.40 mmol) (Example I3) in tetrahydrofuran (4 ml) was added pyridine (0.085 ml, 1.06 mmol). Pentanoyl chloride (0.063 ml, 0.53 mmol) was added under vigorous stirring at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) and ethyl acetate was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. A6 of Table A (0.165 g, 89% yield). 1H-NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.70 (s, 1H), 7.53 (d, 1H), 7.49 (s, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 4.09 (d, 1H), 3.72 (d, 1H), 2.40 (t, 2H), 1.70 (m, 2H), 1.40 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:19])[CH:3]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:22])[CH:17]=2)=[O:11])=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1

Procedure:
In analogy to example 161, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid, MS (ESI+): m/z=288.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.N12CCCN=C1CCCCC2.[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31](S(C)(=O)=O)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31]([O:6][C@H:4]3[C@H:3]4[O:7][CH2:8][C@@H:9]([OH:10])[C@H:2]4[O:1][CH2:5]3)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,3aR,6R,6aR)-Hexahydrofuro[3,2-b]furan-3,6-diol (1.84 g) is dissolved in N,N-dimethylformamide (10 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 1.9 mL). A solution of 6-chloro-5-iodo-2-(methylsulfonyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine (2.05 g) in N,N-dimethylformamide (20 mL) is added drop wise and the mixture is stirred for 2 hours at room temperature. The mixture is partitioned between water and ethyl acetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→0:100) to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CCCCCC>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:16][C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:5]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Solvent: CCCCCC
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1
Yield: 89 %

Procedure:
Analogously to Example 1 B)a), by coupling Z-Gly-OH and H-Asp(OtBu)-OMe there is obtained Z-Gly-Asp(OtBu)-OMe, m.p. 92°-95° C.(hexane), yield: 89% of theory.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH3:25][NH:26][O:27][CH3:28]>CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzo[1,3]dioxole-5-carboxylic acid (69 g, 415 mmol) in dimethylformamide (1L) was added di-imidazol-1-yl-methanone (74 g, 1.1 equiv), and the resulting reaction mixture was stirred at ambient temperature for 90 minutes. N,O-Dimethyl-hydroxylamine (43 g, 1.1 equiv) was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours, and then concentrated in vacuo to ¼ of the volume, poured into 5% aqueous sodium hydrogen carbonate (1L), stirred at ambient temperature for 20 minutes, and then extracted with methyl tert-butyl ether (2×300 mL). The combined organics extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting residue was azeotroped with toluene (800 mL) and dried under vacuum for 3 hours. The crude product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[N:13]=2)=[CH:5][CH:4]=1.N>Br>[N:15]1([CH2:14][C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[O:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Agent: Br
Agent: N
Product: Oc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Yield: 58 %

Procedure:
A solution of 0.51 g (2.0 mmol) 1-[2-(4-methoxy-phenyl)-oxazol-4-ylmethyl]-imidazole in 15 ml 47% aqueous hydrobromic acid was stirred at 70° C. for 4 days. The reaction mixture was poured on ice, made basic with concentrated ammonia and extracted with ethyl acetate to yield 0.28 g (58%) raw 4-[4-(imidazol-1-ylmethyl)-oxazol-2-yl]-phenol as tan crystals.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]=2[NH:24][C:25]2[C:26](=O)[CH2:27][CH2:28][CH2:29][CH:30]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1](/[N:5]=[C:26]1\[CH2:27][CH2:28][CH2:29][CH:30]=[C:25]\1[NH:24][C:13]1[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C1CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC/N=C1\CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Follow a procedure similar to that of Preparation 2 except use n-butylamine (0.53 mL, 5.3406 mmol); toluene (7.0 mL); a solution of titanium(IV) chloride (0.1006 g, 0.5303 mmol) in toluene (3.0 mL); stir the resulting solution for 1 hour; then add a solution of 2-((1,1′:3′,1″-terphenyl)-2′-ylamino)-2-cyclohexen-1-one (0.3062 g, 0.9021 mmol, Preparation 7) in toluene (2.0 mL); toluene rinse (1.0 mL); to afford after isolation 0.3352 g (94.18%) of the product (J) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1c[nH]cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.0 g) and pyridine hydrochloride (390 mg) were dissolved in methanol (8 ml). The solution was stirred at 60° C. for 2 h. The solution was cooled and neutralized with saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled off and the residue was filtered and washed with ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=30:1→10:1), then recrystallized from ethyl acetate to give the titled compound (454 mg) as a colorless powder.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[C:32]1([C:38]2[NH:42][N:41]=[C:40]([SH:43])[N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([C:38]2[NH:42][N:41]=[C:40]([S:43][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[N:39]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCSc2n[nH]c(-c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 5-phenyl-1H-1,2,4-triazole-3-thiol, the title compound was obtained as a white powder (1.01 g, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](COCc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.3 %

Procedure:
Dissolve (R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 mg, 10.5 mmol) in anhydrous THF (50 mL). Add sodium hydride (60% in mineral oil, 480 mg, 12 mmol) and stir at 0° C. for 30 min. Add 4-fluorobenzyl bromide (1.5 mL, 12 mmol) followed by tetrabutylammonium iodide (370 mg, 0.1 mmol) and stir for 72 h at ambient temperature. Pour the mixture into water (500 mL), extract with DCM (3×150 mL), wash with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a yellow oil (2.18 g, 77%).
Reaction SMILES: [CH:1]1([C:5]([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)[CH2:4][CH2:3][CH2:2]1.C([N:19](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O.C1(C)C=CC=CC=1>[C:1]1(=[C:5]2[NH:19][C:10](=[O:11])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1SC(=O)C1CCC1
Reactant: CCN(CC)CC
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=C2CCC2)Sc2ccccc21
Temperature: -15 °C
Yield: 40.2 %

Procedure:
2-[(Cyclobutylcarbonyl)thio]benzoic acid (9.01 g, 38 mmol) was suspended in acetone (150 ml). While stirring under ice cooling, triethylamine (4.25 g, 42 mmol) and then ethyl chloroformate (4.88 g, 45 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (15 ml) of sodium azide (2.92 g, 45 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −15° C. and a solution (15 ml) of tributylphosphine (7.70 g, 38 mmol) in toluene was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was recrystallized from toluene-isopropyl ether to give the title compound (3.32 g, 40%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH:13]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1cccc2c(CC(C)=O)coc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc2c(CC(C)N3CCN(c4cccc5cccnc45)CC3)coc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, the reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.14 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.46˜6.80 (m, 8H); 4.01 (s, 3H); 3.51˜1.60 (m, 11H); 1.14(d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH3:8][CH2:9][O-:10].[Na+].[CH2:12]([OH:14])C>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:12]([O:10][CH2:9][CH3:8])=[O:14])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2]
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CCl
Product: CCOC(=O)CC(=O)OCC

Procedure:
As in Example 1, but in a pressure vessel with a capacity of 18 liters equipped with a pH measuring system, 3.06 kg (25 moles) of chloroacetic acid ethyl ester, 1 liter of ethanol and 125 g of Co2 (CO)8 are combined at 5 at. CO. At a reaction temperature of 55° C., 7.03 kg of 21.9% sodium ethylate (22.6 moles) is pumped in over a period of 51/2 hours, at a pH of 7.0. 3.43 kg of malonic acid diethyl ester is obtained (yield 95%) plus 290 g of chloroacetic acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1

Procedure:
A solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)=O
Reactant: Nc1ccc(I)cc1
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 retool) was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 retool) and sodium triacetexyborohydride (13.8 g, 65 retool). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 retool) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) and the layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-aminooctane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]3[CH:2]=2)=[CH:6][C:7]=1[I:12]
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(O)c(I)c1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(O)c(I)c3)cn2c1
Temperature: 105 °C
Yield: 59.8 %

Procedure:
680 mg (corresponding to 1.99 mmol) of 2-bromo-4′-hydroxy-3′-iodoacetophenone and 252 mg (corresponding to 2.03 mmol) of 2-amino-5-methoxypyridine were dissolved in 15 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 105° C. for 4 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 5 mL of water and 5 mL of methanol. Then, about 5 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 435 mg (corresponding to 1.19 mmol) of 2-(4′-hydroxy-3′-iodophenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 3, Step 6).
Reaction SMILES: [Si]([O:8][C:9]1([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[C:17]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:42][C:41]7[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=7)[C:35]6=[O:43])[C:29]=5[CH3:44])=[CH:18][CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]=4[NH:22]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[C:17]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:42][C:41]7[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=7)[C:35]6=[O:43])[C:29]=5[CH3:44])=[CH:18][CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]=4[NH:22]3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C5(O[Si](C)(C)C(C)(C)C)CC5)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C5(O)CC5)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Step 4 A solution of 7-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (0.039 g, 0.065 mmol) in THF (0.66 mL) was treated with tetra-n-butylammonium fluoride (1 M in THF, 0.098 mL, 0.098 mmol). After 10 min, the mixture was combined with an identical reaction mixture done on 22% of the scale described, and the mixture was concentrated. The residue was purified by preparative HPLC. The appropriate effluent fractions were treated with NaHCO3 (aq) and partially concentrated. The aqueous residue was extracted three times with DCM and the combined organic phases were dried and concentrated to give 7-(1-hydroxycyclopropyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (23.3 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ 11.42 (1 H, s), 8.18 (1 H, br. s.), 7.98 (1 H, d, J=7.7 Hz), 7.80 (1 H, d, J=7.7 Hz), 7.72 (1 H, s), 7.68 (2 H, d, J=3.8 Hz), 7.60 (1H, d, J=7.7 Hz), 7.56 (1 H, ddd, J=7.8, 4.1, 4.0 Hz), 7.49 (2 H, t, J=7.7 Hz), 7.33 (1H, d, J=7.1 Hz), 7.01 (1 H, d, J=7.7 Hz), 6.95 (1 H, d, J=8.2 Hz), 6.79 (1 H, d, J=8.2 Hz), 5.95 (1 H, s), 4.90-5.02 (2 H, m), 1.84 (3 H, s), 1.07-1.15 (2 H, m), 0.91-1.00 (2 H, m). Mass spectrum m/z 488.3 (M+H)+.
Reaction SMILES: COC(=O)N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CC1C=C2C(C)=NN(C)C2=NC=1N(CC1CCCC1)CC.[C:42]([O:46][C:47](=[O:81])[CH2:48][N:49]([CH2:66][C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:80])([F:79])[F:78])[CH:68]=1)[CH2:50][C:51]1[C:52]([C:61]#[C:62][CH2:63][CH2:64][CH3:65])=[N:53][C:54]2[C:59]([CH:60]=1)=[CH:58][CH:57]=[CH:56][CH:55]=2)([CH3:45])([CH3:44])[CH3:43]>C(O)C.[Pd]>[C:42]([O:46][C:47](=[O:81])[CH2:48][N:49]([CH2:66][C:67]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[C:69]([C:77]([F:78])([F:79])[F:80])[CH:68]=1)[CH2:50][C:51]1[C:52]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[N:53][C:54]2[C:59]([CH:60]=1)=[CH:58][CH:57]=[CH:56][CH:55]=2)([CH3:43])([CH3:44])[CH3:45]
Reactant: CCCC#Cc1nc2ccccc2cc1CN(CC(=O)OC(C)(C)C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)c(C)nn2C
Solvent: CCO
Product: CCCCCc1nc2ccccc2cc1CN(CC(=O)OC(C)(C)C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 44 %

Procedure:
The compound obtained in Example 16, [(3,5-bis-trifluoromethyl-benzyl)-(2-pent-1-ynyl-quinolin-3-ylmethyl)-amino]-acetic acid tert-butyl ester (163 mg, 0.3 mmol) was dissolved in ethanol (3 mL), and palladium [10% on carbon powder (50 mg)] was added. The resulting mixture was stirred under H2 (using a balloon) for 3 h. The sample was diluted in ethanol and filtered through Celite™. The Celite™ was washed with ethanol, the filtrate was concentrated by rotary evaporation, and the resulting sample was dried overnight under vacuum and the crude was purified (Biotage Horizon HPFC chromatography system, SiO2, 80:20 hexanes:ethyl acetate) to give the titled product as a colorless oil (75 mg), yield: 45%, of 96.3% purity (HPLC: Inertsil ODS-3V C18, 20:80 [KH2PO4 (0.01M, pH 3.2):CH3CN], 264 nm, Rt 49.0 min)