Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:42][CH2:43][O:44][Si](C)(C)C(C)(C)C)[C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])=[CH:19][C:18]([C:38]([CH3:41])([CH3:40])[CH3:39])=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CO.O.C(Cl)Cl>[OH:6][CH2:7][CH2:8][N:9]([CH2:42][CH2:43][OH:44])[C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[CH:27][CH:26]=3)=[O:23])=[CH:19][C:18]([C:38]([CH3:39])([CH3:40])[CH3:41])=[N:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(N(CCO)CCO)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a solution of 1-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (124 mg, 0.28 mmol), (tert-butyldimethylsilyloxy)acetaldehyde (135 mg, 0.70 mmol, 2.5 eq), and sodium triacetoxyborohydride (178 mg, 0.84 mmol, 3 eq) in anhydrous THF (2 mL) was added acetic acid (20 mg, 0.34 mmol, 1.2 eq). The reaction was stirred under N2 at room temperature for 2 h. The reaction mixture was quenched with saturated aq NaHCO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated at reduced pressure. The residue was purified by MPLC (eluting with 45:55 to 65:35 EtOAc/hexanes) to give 153 mg (72%) of 1-[2-(3-{bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea. 1H-NMR (DMSO-d6) δ 9.17 (s, 1H), 8.39 (d, J=6.3 Hz, 2H), 8.31 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.24 (t, J=7.9 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 6.84 (d, J=6.1 Hz, 2H), 6.72-6.66 (m, 3H), 6.33 (s, 1H), 3.72 (t, J=5.8 Hz, 4H), 3.49 (t, J=5.9 Hz, 4H), 1.26 (s, 9H), 0.82 (s, 18H), −0.01 (s, 12H); MS LC-MS [M+H]+=760.3, RT=4.10 min. Step 2: To a solution of 1-[2-(3-{bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (153 mg, 0.20 mmol) in methanol (2 mL) was added a solution of 10% TFA in H2O (2 mL). The reaction was stirred at room temperature for 4 h. The mixture was then diluted with DCM, basified by addition of saturated NaHCO3 and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, and concentrated at reduced pressure. The residue was purified by MPLC (eluting with 3% to 6% MeOH in DCM) to give 35 mg (36%) of the desired product. 1H-NMR (DMSO-d6) δ 9.17 (s, 1H), 8.40 (dd, J=1.5 & 4.7 Hz, 2H), 8.32 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.26-7.22 (m, 1H), 7.07 (d, J=9.1 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.71-6.69 (m, 2H), 6.63 (d, J=7.9 Hz, 1H), 6.34 (s, 1H), 4.76 (t, J=5.4 Hz, 2H), 3.54 (q, J=5.7 Hz, 4H), 3.43 (t, J=5.7 Hz, 4H), 1.26 (s, 9H); MS LC-MS [M+H]+=531.2, RT=2.27 min.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([N+:22]([O-])=O)[N:4]=1)[CH3:2].[NH4+].[Cl-].CCOC(C)=O>CO.C1COCC1.[Zn]>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[CH3:2]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(N)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of crude 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.038 g, 3.19 mmol) in MeOH (12 mL) and THF (12 mL) was treated with NH4Cl (6.83 g, 128 mmol), cooled to 0° C., treated portion-wise with zinc dust (2.08 g, 31.9 mmol) and stirred overnight as the cooling bath expired. The mixture was treated with EtOAc, the solids removed via filtration through diatomaceous earth, washed well with warm EtOAc and the filtrate concentrated to dryness. The residue was treated with EtOAc, heated to near-reflux, filtered to remove solids and the filtrate concentrated to dryness. The collected solids were treated again with EtOAc, heated to reflux and filtered hot to afford a white solid. The concentrated filtrate was purified via silica gel chromatography (MeOH/EtOAc) and combined with the solid isolated above to afford 6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (483 mg, 51%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.7 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.18-7.16 (m, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.50-6.49 (m, 1H), 6.36-6.34 (m, 1H), 5.95-5.93 (m, 2H), 3.84 (s, 3H), 2.40-2.38 (m, 2H), 1.04 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 296.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)(O)[O-].[Na+].[I-].[Na+]>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][NH:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:15])([F:1])[CH:12]([F:13])[F:14])=[CH:6][CH:7]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: Nc1ccc(OCC(F)(F)C(F)F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Yield: 78.9 %

Procedure:
A mixture of 8.6 g of 4-(2,2,3,3-tetrafluoropropoxy)aniline, 4.8 g of ethyl chloroacetate, 4.8 g of sodium bicarbonate, 3.0 g of sodium iodide and 300 ml of acetone was refluxed for 21 hours. The solvent was distilled off under reduced pressure and 200 ml of ice water and 200 ml of dichloromethane were added to the residue to fractionate. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane [1:3 v/v]) to give 9.4 g of N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.ClC(OC)=O.CCN(CC)CC>CO>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1ccc(NC(=O)Nc2c(F)ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (790 mg, 1.71 mmol, 1.0 equiv) in MeOH (5 mL) was added by syringe HCl (4.0 M in dioxane, 4.5 mL, 17 mmol, 10 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in DCM (20 mL) and methyl chloroformate (158 μL, 2.05 mmol, 1.2 equiv) and Et3N (716 μL, 5.13 mmol, 3.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 1.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by preparative thin layer chromatography (10% MeOH/DCM) to provide methyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (275 mg, 38%). LCMS m/z (APCI)=420.2 (M+H).
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([O:24]C(=O)CC)[CH:22]=[CH:23][C:17]=4[C:16]=3[C:29](=[O:45])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:32][CH:31]=3)=[CH:11][CH:10]=2)C[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O>>[OH:24][C:21]1[CH:22]=[CH:23][C:17]2[C:16]([C:29](=[O:45])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:34][CH:35]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)[S:19][C:18]=2[CH:20]=1
Reactant: CCC(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC4CCCCCC4)cc3)sc2c1
Agent: O=C[O-]
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(OC3CCCCC3)cc2)sc2cc(O)ccc12

Procedure:
2-(4-cycloheptyloxyphenyl)-6-propionyloxy-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, formate
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25](Cl)=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O1CCOCC1>[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCC1Cc2ccc(C(=O)NCC(=O)O)cc2C1
Yield: 66.5 %

Procedure:
1.10 g (14.7 mM) of glycine, 0.29 (7.25 mM) of NaOH, 5.8 ml of distilled water were placed in a 100 ml-three necked flask and dissolved to prepare a solution. To the solution, 5.8 ml of dioxane was added, followed by stirring or a ice-common salt bath. To the mixture, a solution of 0.29 g (7.25 mM) of NaOH in 2.5 ml of distilled water and a solution of 2.14 g (7.29 mM) of 2-octylindan-5-carbonyl chloride in 10 ml of dioxane were gradually added dropwise at the same time at -1° to 3° C. by means of a dropping funnel, respectively, followed by stirring for 30 minutes at 1°-2° C. After the reaction, 0.87 ml of concentrated HCl was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying and recrystallization from methanol to obtain 1.61 g of N-(2-octylindan-5-carbonyl)glycin (Yield: 66.6%).
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:17]([O:21][C:22]([N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:25][C:26]([N:14]1[CH2:13][CH2:12][N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:16][CH2:15]1)=[O:27])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Reactant: CCCCCCCCCCN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCN1CCN(C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
A 2.3 g (8.64 mmoles) quantity of N,N,-dicyclohexylcarbodiimide was added to 20 ml of a solution of 2.0 g (7.35 mmoles) of N-decylpiperazine, 1.9 g (7.56 mmoles) of N-t-butoxycarbonylphenylglycine, 1.3 g (15.5 mmoles) of sodium hydrogen carbonate and 122 mg (1.0 mmole) of 4-dimethylaminopyridine in anhydrous methylene chloride. The mixture was stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with methylene chloride. Mother liquor and the washings were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=15:1), giving 2.8 g (yield: 83%) of 1-(N-t-butoxycarbonylphenylglycyl)-4-decylpiperazine.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:4]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CCCNC1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)piperidine-1-carboxylate (1.5 g) in dichloromethane (10 ml) was stirred at room temperature. A 4M solution HCl in dioxane (20 ml) was added and the mixture was stirred for 30 minutes. The mixture was filtered and washed with dichloromethane and then diethyl ether. This gave 1-(piperidin-3-ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperazine hydrochloride as a white solid (1.3 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C@H:8]([NH2:30])[CH2:9][C@@H:10]1[C@@H:14]([OH:15])[C@@H:13]([O:16]CC#C)[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH2:29])[O:11]1)[C:3]([OH:5])=[O:4]>CO.O.CC(O)=O>[CH:23]1[N:24]=[C:25]([NH2:29])[C:26]2[N:27]=[CH:28][N:20]([C@@H:12]3[O:11][C@H:10]([CH2:9][C@@H:8]([NH2:30])[CH2:7][CH2:6][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[C@@H:14]([OH:15])[C@H:13]3[OH:16])[C:21]=2[N:22]=1
Reactant: C#CCO[C@@H]1[C@H](O)[C@@H](C[C@@H](N)CC[C@H](N)C(=O)O)O[C@H]1n1cnc2c(N)ncnc21
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C[C@@H](N)CC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O

Procedure:
The title detection analyte compound was prepared from Compound 7 (Example 1, Step 3a) by coupling with 6-carboxyfluorescein-PEG3 azide (Berry & Associates, CAS #412319-45-0, Catalog No. FF6110) using the click chemistry methods reported herein; LC/MS (Gemini C18, 3μ, 2.0×50 mm, 400 μL/min, A: 90/10/0.01 H2O/MeOH/HOAc, B 90/10/0.01 MeOH/H2O/HOAc 0-6 min 0-100% B, 6-9 hold at 100% B, 9.1-15 min re-equilibrate at 0% B) 4.3 min (100% purity), ESI+ m/z 498 (z=2; expected molecular mass: 996).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][CH:34]([F:36])[F:35])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][CH:34]([F:35])[F:36])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)NC(=O)OC(C)(C)C)[nH]3)c2nc1NCC(F)F
Temperature: 110 °C

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (950 mg, 1.887 mmol) and LiOH monohydrate (396 mg, 9.43 mmol) in dioxane (8.0 mL) and water (4.00 mL). The reaction mixture was stirred and heated in at 110° C. for 80 min. LC-MS indicated >87% conversion to the desired carboxylic acid m/z (ESI, +ve ion) 476.1 (M+H)+. The reaction mixture was transferred to a 250 mL RBF, using MeOH and concentrated to dryness affording 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid as an orange solid. The orange solid was treated with 4.0 M HCl solution in 1,4-dioxane (11.79 mL, 47.2 mmol) at RT and stirred for 30 min. The reaction mixture was concentrated to give 2-(1-aminoethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (382b) as a red-orange solid. It was used in the subsequent step without further purification assuming quantitative yield. 19F NMR (377 MHz, DMSO-d6) δ ppm −120.68 (1F, s). (m/z (ESI, +ve ion) 376.1 (M+H)+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][CH:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])O.[Na+]>>[CH3:13][CH:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:8]=[O:9])=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[CH3:11]
Reactant: CC(C)N1CCCc2ccccc21
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
18.6 g (0.12 mol) of phosphorus oxychloride was dropped into 29.2 g (0.4 mol) of N,N-dimethylformamide under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes and cooled again on an ice bath. 17.5 g (0.1 mol) of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline was gradually dropped into the resulting mixture. The mixture thus obtained was stirred at room temperature for one hour and poured onto ice-water. The resulting mixture was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate/n-hexane) to give 11.4 g of the title compound as a reddish-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([OH:18])[N:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)O)[CH:23]=[CH:22][N:21]=[CH:20]1.FC1C=CC(CCC2C=CC(OC(C3C=CC(F)=CC=3)CC3N(C)C=NC=3)=CC=2C([O-])=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([O:18][CH:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)nc1-c1ccc(F)cc1
Reactant: OC(Cn1ccnc1)c1ccc(F)cc1
Agent: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)[O-])c1)c1ccc(F)cc1
Product: COC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)nc1-c1ccc(F)cc1

Procedure:
Methyl 2-(4-fluorophenyl)-6-hydroxypyridin-3-carboxylate was reacted with 2-(imidazol-1-yl)-1-(4-fluorophenyl)ethanol by the procedure described for the preparation of 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoate to give methyl 2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]pyridin-3-carboxylate.
Reaction SMILES: Cl[N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:3]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][N:2]=1
Reactant: C1CNCCN1
Reactant: ClN1C=Cc2ccccc2C1
Solvent: Cc1ccccc1
Product: c1ccc2c(N3CCNCC3)nccc2c1
Temperature: 0 °C
Yield: 105.6 %

Procedure:
A solution of 2-chloroisoquinoline (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene. The solution is heated for an additional 48 h. After cooling to 0° C. for 0.5 h, the solution is filtered. The filtrate is then extracted with 10% acetic acid. The aqueous extracts are washed with ether, basified and subsequently extracted with dichloromethane. The dichloromethane layer is finally washed with water, dried and concentrated. The material is placed under vacuum overnight to yield the title compound (6.8 g, m.p. 54-56° C.). 1H NMR (CDCl3) 8.14 (d, J=5.5 Hz, 1 H), 8.10 (d, J=8.5 Hz, 1 H), 7.74 (d, J=8.5 Hz, 1 H), 7.60 (t, J=7.2 Hz, 1 H), 7.50 (t, J=7.6 Hz, 1 H), 7.24 (d, J=5.5 Hz, 1 H), 3.39 (t, J=5.0Hz, 4 H), 3.16 (t, J=5.0Hz, 4 H).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:40]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:41]([O:43][CH2:44][CH2:45][CH3:46])=[O:42]>C(O)C.[Ni]>[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH:26][CH:40]([C:41]([O:43][CH2:44][CH2:45][CH3:46])=[O:42])[CH2:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CCCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1

Procedure:
L-Alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate (4.1 g) is dissolved in 40 ml of ethanol, then 0.85 g of sodium acetate, 2 ml of acetic acid, 5 g of propyl 2-oxo-4-phenylbutyrate and 5 g of molecular sieve 3A are added, thereafter a suspension of 6 g of Raney nickel in 20 ml of ethanol is added, and catalytic reduction is carried out at ordinary temperature and ordinary pressure. When the hydrogen absorption has ceased, the supernatant is separated by decantation. The precipitate is washed two or three times with ethanol. The supernatant and the washings are combined, and the solvent is distilled off under reduced pressure. The residue is shaken with 100 ml of ethyl acetate and aqueous sodium hydrogen carbonate. Filtration with 10 g of diatomaceous earth, separation of the ethyl acetate layer of the filtrate, washing with water, drying and removal of solvent by distillation give N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-glycine tert-butyl ester as a slightly yellow, viscous oil. To this are added 3 ml of acetic acid and 12 ml of 25% hydrobromic acid solution in acetic acid, and the mixture is shaken occasionally for 15 minutes so as to make the reaction proceed. On adding 150 ml of ethyl ether, crystalline precipitate forms, which is collected by filtration to give 3.4 g of N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrobromide as colorless crystals. They are added to a mixture of 70 ml of water and 70 ml of ethyl acetate, and the mixture is stirred, neutralized with sodium hydrogen carbonate and then adjusted to pH 3-4 with 10% hydrochloric acid. The ethyl acetate layer is separated, dried over anhydrous magnesium sullfate, and made acidic with ethanolic hydrochloric acid. The solvent is distilled off, and 150 ml of ethyl ether is added to the residue. After allowing the mixture to stand for 10 minutes, the resulting crystalline precipitate is collected by filtration to give 1.7 g of N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride melting at 147°-150° C. with decomposition.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]2=[O:22])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Schemes 1 and 2, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with 1,3-Dihydro-benzoimidazol-2-one (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzoic acid methyl ester.