Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.C[Al](C)C.C[O:19][C:20]([C:22]1[N:23]=[C:24]([CH2:68][CH2:69][CH3:70])[N:25]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=2)[C:26]=1[C:27]([O:29][CH3:30])=[O:28])=O>CCOCC.C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]([C:26]1[N:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:36][CH:37]=2)[C:24]([CH2:68][CH2:69][CH3:70])=[N:23][C:22]=1[C:20]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:19])=[O:28]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCc1nc(C(=O)N2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 0.72 g (4.4 mmol) of 1-(2-pyridyl)piperazine in 10 mL of anhydrous CH2C12 under N2 was added 4.4 mL (4.4 mmol) of a 1 N solution of HCl in ether. After 15 min., the suspension was cooled to 10° C. and treated with 2.2 mL (4.4 mmol) of 2.0 M Me3Al in toluene. Slow gas evolution was noted. After 30 min., a solution of 2.81 g (4.00 mmol) of 4,5-bis(methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole in 12 mL of CH2C12 was added. The reaction mixture was allowed to warm to room temperature and stir for 2 h, then partitioned between EtOAc and H2O. The water layer was washed with EtOAc and the combined organic extracts were washed with water and brine, then dried over MgSO4. After removal of solvents at reduced pressure, the residual tan foam (4.08 g) was purified using flash chromatography (eluent: 50/50 EtOAc-hexane to 1% MeOH-EtOAc) to give 2.36 g (71%)of the title compound as a white foam. 1H NMR (300 MHz, CDCl3): δ0.88 (t, J=7.5 Hz, 3H, CH3); 1.70 (sextet, J=7.5 Hz, 2H, CH2); 2.52 (t, J=7.5 Hz, 2H, CH2); 3.45 (m, 2H, piperazine); 3.54 (m, 2H, piperazine); 3.63 (m, 2H, piperazine); 3.71 (s, 3H, CO2CH3); 3.93 (m, 2H, piperazine); 5.46 (s, 2H, benzyl); 6.67 (m, 2H, aromatic); 6.82 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 6.94 (d, J=7.5 Hz, 6H, trityl); 7.11 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 7.2-7.4 (m, 10H, aromatic); 7.4-7.5 (m, 3H, aromatic); 7.91 (dd, J=7.0, 6.0 Hz, 1H, tetrazolyl-phenyl); 8.19 (approx. dd, J=5.5, 2.0 Hz, 1H, pyridyl).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH:42][CH3:43])=[O:41])[CH:38]=5)[C:33]([CH3:44])=[CH:32][C:31]4=[O:45])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH:42][CH3:43])=[O:41])[CH:38]=5)[C:33]([CH3:44])=[CH:32][C:31]4=[O:45])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 5.5 h

Procedure:
To 0.5 mL of methanol solution containing 58 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-7-((methylamino) carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 5.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.032 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-N-methyl-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxamide hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].Cl.[F:32][C:33]([F:41])([F:40])[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:21][C:6]1[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:37]3[CH2:38][CH2:39][CH:34]([C:33]([F:41])([F:40])[F:32])[CH2:35][CH2:36]3)=[O:30])=[CH:24][CH:23]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
Treat a solution of 3′,5′-dichloro-4′-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.25 g, 0.56 mmol), 4-(trifluoromethyl)piperidine hydrochloride (0.13 g, 0.67 mmol), 1-hydroxybenzotriazole (0.23 g, 0.67 mmol), and 4-methylmorpholine (0.18 mL, 1.67 mmol) in dichloromethane (10 mL) with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.13 g, 0.67 mmol) and stir at room temperature for 6 hr. Quench the reaction with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel column chromatography using hexanes:ethyl acetate to afford 0.23 g (72%) of desired product: MS (m/z): 583 (M+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(N(CC)CC)C>O1CCCC1>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(CCCCl)CC2
Yield: 52.6 %

Procedure:
A mixture of 7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 7.3 mmol), 1-bromo-3-chloropropane (0.80 ml, 8.1 mmol) and triethylamine (3 ml, 21.5 mmol) in anhydrous tetrahydrofuran (25 ml) was heated at reflux for 5 h. The mixture was cooled, evaporated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml) and the combined organics washed with brine (150 ml), dried (Na2SO4) and evaporated in vacuo. Purification by chromatography on silica gel using 10-70% ethyl acetate in hexane gradient elution gave the title compound as a pale orange oil (1.22 g, 53%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].O1CCCC1.Cl>[OH-].[Na+]>[CH3:13][S:14]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
To a solution of L-phenylalanine 1.65 g (10 mmol) in 2N sodium hydroxide aqueous solution, cooled in an ice-water bath and under vigorous stirring, a mixture of methanesulfonyl chloride 1.26 g (11 mmol) and tetrahydrofuran 3 ml, and 2N sodium hydroxide aqueous solution 6 ml were added dropwise and alternately each in three portions. After completion of addition stirring was continued under ice-water cooling for 5 minutes, further, at room temperature for 1 hour. 6N hydrochloric acid 2 ml was added, and extraction was made with 30 ml of chloroform. Organic layer was washed with water and dried, and the solvent distilled off to obtain crude N-Ms-L-Phe as an oil. The crude product was purified by silica gel column chromatography- (eluent: chloroform, ethyl acetate) to give pure N-Ms-L-Phe 1.00 g as an oil. The yield based on the used L-phenylalanine was 41.0%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (48 mg, 73%), MS (ISP) m/z=413.4 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:50][C:51]2[C:52]([C:63](=[O:64])[NH2:65])=[C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:54]=[CH:55][CH:56]=2)=[O:16])[N:13]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)O)cs1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1nc(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To a solution of 2-(N-tert-butylsulfamoyl)thiazole-4-carboxylic acid (0.56 g, 2.1 mmol) in DCM (50 mL) was added HATU (1.41 g, 2.8 mmol) and DIPEA (1.04 ml, 5.6 mmol). The reaction mixture was stirred at room temperature for 1 h and then 3-aminobiphenyl-2-carboxamide (from example 218, 0.3 g, 1.4 mmol) was added. The resulting solution was stirred for an additional 16 h. After this time, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (30% EtOAc in hexane) to provide 2-(N-tert-butylsulfamoyl)-N-(2-carbamoylbiphenyl-3-yl)thiazole-4-carboxamide (0.11 g, 17% yield) as white solid. LCMS Method V: retention time 1.85 min; [M+1]=459.2.
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[N:38]1C=C(B(O)O)C=[N:40][CH:39]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:38][CH:39]=[N:40][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:35])[F:34]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cncnc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using pyrimidin-5-ylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])C(O)=O)=[CH:12][CH:11]=1)([O-:3])=[O:2].[N+](C1C=CC=CC=1C1C=CC=CC=1)([O-])=[O:22].C(Cl)(=O)C>>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH:12]=1)(=[O:22])[CH3:20]
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
The 2-(2'-nitro-4-biphenylyl)propionic acid is readily prepared in the following manner: 2-nitrobiphenyl is acylated with acetyl chloride, giving 4-acetyl-2'-nitrobiphenyl. This is converted with chloroacetonitrile under alkaline conditions to the intermediate isomeric 2-methyl-2-[4-(2'-nitrophenyl)]glycidonitriles which, when treated with lithium perchlorate and then base, is isomerized to methyl 2-(2'-nitro-4-biphenylyl)propionate. Saponificiation of the latter gives the desired 2-(2'-nitro-4-biphenylyl)propionic acid. The esters are readily converted to the acid and the acid to the esters by conventional means.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:15]1[C:16]2[C:12](=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ccc23)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
4-(5-Nitropyridin-2-yloxy)-1H-indole (3.34 g, 13.1 mmol) was dissolved in DMF (20 mL). To the solution were added 60% sodium hydride (0.523 g, 13.1 mmol) and ethyl bromoacetate (1.45 mL, 13.1 mmol) under cooling with ice, and the resulting solution was stirred for 1 hour. Ice water (150 mL) was added to the solution, and the mixture was extracted with ethyl acetate (150 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. Thus obtained residue was purified by silica gel column chromatography (AcOEt:n-hexane=1:3), and then the obtained solid was recrystallized from ethyl acetate and n-hexane to yield 1.84 g of the title compound as a yellow powder.
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]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](O)[CH3:16].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-naphthalenecarboxylic acid (Compound M) 3.1 g, (12.43 mmol) in ethanol (30 ml, 23.55 g, 511.0 mmol) was added 18M sulfuric acid (2 ml). The solution was refluxed for 30 minutes, cooled to room temperature, and the reaction mixture partitioned between pentane (100 ml) and water (100 ml). The aqueous, phase was extracted with pentane (100 ml) and the combined organic layers washed with saturated aqueous NaCl (100 ml), dried (MgSO4), and concentrated to yield an off-white solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as a white solid. 1H NMR (CDCl3): δ8.58 (1H, br s), 8.10 (1H, dd, J=1.7, 9 Hz), 8.06 (1H, d, J=2 Hz), 7.83 (1H, d, J=9 Hz), 7.80 (1H, d, J=9 Hz), 7.62 (1H, dd, J=2, 9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[C:27](/[CH3:32])=[CH:28]/[C:29](O)=[O:30])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[C:27](/[CH3:32])=[CH:28]/[C:29]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:30])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C)c1

Procedure:
0.46 g of compound 3 was obtained in a similar manner to those described in the Example 1 and 2 using 2.16 g of ethyl 4-(2-aminophenoxy)butyrate and 1.04 g of 3-(1-methylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.Cl.[CH:13]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2.CCN(CC)CC>C(#N)C>[CH:16]12[N:19]([C:2]3[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=3)[CH:13]([CH2:18][CH2:17]1)[CH2:14][CH2:15]2
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(N2C3CCC2CC3)ncc1N
Temperature: 80 °C
Yield: 81.9 %

Procedure:
To a solution of 2-fluoro-4-methyl-5-nitropyridine (150 mg, 0.9608 mmol) in acetonitrile (5 mL) was added 7-azabicyclo[2.2.1]heptane hydrochloride (152.9 mg, 1.153 mmol) and Et3N (243.1 mg, 334.8 μL, 2.402 mmol). The reaction was heated at 80° C. for 16 h. The reaction was quenched with water (2 mL) and solvent was evaporated. The residue was dissolved in ethyl acetate (15 mL), washed with 1N HCl (10 mL), dried over MgSO4, filtered and concentrated to afford 6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methylpyridin-3-amine (160 mg, 71% yield) as yellow solid which was used in next step without purification. 1H NMR (400.0 MHz, CDCl3) δ 8.96 (s, 1H), 6.37 (s, 1H), 4.59 (s, 2H), 2.59 (d, J=0.4 Hz, 3H), 1.83-1.80 (m, 4H), 1.61-1.54 (m, 4H).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B>C1COCC1>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[SH:1]
Reactant: O=C(O)c1ccncc1S
Agent: B
Solvent: C1CCOC1
Product: OCc1ccncc1S
Reaction time: 0.5 h

Procedure:
To a suspension of 3-mercaptoisonicotinic acid (1.80 g, 11.6 mmol) in dry THF (70 mL) was added slowly borane in THF (52 mL, 1 M, 52 mmol) and the reaction mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, methanol (40 mL) was added, and after gas evolution stopped, concentrated hydrochloric acid (3.6 mL) was added. The solution was filtered and the filtrate was evaporated to dryness. The residue was redissolved in a small volume of water, concentrated aqueous ammonia (3.6 mL) was added and the reaction mixture was evaporated to dryness. After overnight drying under vacuum, a quantitative yield of the title product was obtained, which was used for the next step without purification. 1H NMR (CD3OD) δ 4.78 (s, 2H), 8.13 (d, 2H, J=6), 8.60 (d, 2H, J=6), 8.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)=[O:28])=[N+:22]=[N-:23]>>[CH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[C:27]([NH:26][CH2:25][CH2:24][N:21]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=2)[N:23]=[N:22]1)=[O:28]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc4ccccc4c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.095 g, 0.344 mmol) was reacted with N-(2-azidoethyl)-2-naphthamide (0.083 g, 0.344 mmol) following the general click procedure to give tert-butyl 4-(5-(1-(2-(2-naphthamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), δ 8.01 (s, 1H), δ 7.72 (m, 4H), δ 7.39 (m, 2H), δ 7.26 (s, 1H), δ 6.33 (s, 1H), S 6.04 (s, 2H), δ 4.51 (s, 2H), δ 3.88 (s, 2H), δ 2.48 (t, 2H), δ 2.12 (s, 2H), δ 1.47 (m, 13H), δ 1.17 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 150.4, 149.5, 148.3, 138.6, 134.9, 132.7, 131.4, 129.2, 128.5, 128.1, 127.9, 126.8, 124.0, 122.3, 106.5, 84.9, 49.4, 40.4, 29.9, 29.2, 28.9, 28.6, 28.2, 27.9, 28.6, 27.9, 27.8, 25.6 ppm; HRMS (ESI) calcd for C28H35N7O3(M+) 517.2801. found 517.2792, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-naphthamide hydrochloride (0.140 g, 90% yield). 1H NMR (300 MHz, CD3OD) δ ppm; 13C NMR (75 MHz, CD3OD) δ ppm; HRMS (ESI) calcd for C23H27N7O (M+) 417.2277. found 417.2274.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[O:16]1[CH2:17][CH2:18][CH2:19][C@H:14]([NH:13][C:5]2[C:4]([NH2:1])=[CH:9][N:8]=[C:7]3[CH:10]=[CH:11][S:12][C:6]=23)[CH2:15]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CCCOC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2ccsc2c1N[C@H]1CCCOC1

Procedure:
A mixture of 6-nitro-N-[(3S)-tetrahydro-2H-pyran-3-yl]thieno[3,2-b]pyridin-7-amine (30 mg, 0.1 mmol), iron (18 mg, 0.32 mmol) and ammonium chloride (29 mg, 0.54 mmol) in ethanol (0.8 mL)/water (0.3 mL) was heated at reflux for 4 h. The resulting mixture was filtered. The filtrate was diluted with EtOAc, washed with sat. NaHCO3 solution, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C12H16N3OS (M+H)+: m/z=250.1. Found: 250.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[Cl:10].[Mg].[Cl:12][CH2:13][CH:14]1[CH2:16][O:15]1.Cl>O(CC)CC>[Cl:10][C:4]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=1[CH2:2][CH2:16][CH:14]([CH2:13][Cl:12])[OH:15]
Reactant: ClCC1CO1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)CCc1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 98 parts of 1-(chloromethyl)-2,4-dichlorobenzene and 14 parts of magnesium in 70 parts of 1,1-oxybisethane, is added dropwise a solution of 46.5 parts of 2-(chloromethyl)oxirane in 350 parts of 1,1'-oxybisethane. Upon completion, stirring at reflux temperature is continued overnight. The reaction mixture is cooled in an ice-bath and decomposed by dropwise addition of 120 parts of a concentrated hydrochloric acid solution. The whole is poured onto water and the layers are separated. The organic phase is washed three times with water. The aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are dried, filtered and evaporated. The residue is distilled, yielding 2,4-dichloro-α-(chloromethyl)benzenepropanol; bp. 130° C. at 0.04 mm. pressure.