Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:44][C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)=[O:46]>CC#N.CC#N.CN(C=O)C>[O:46]=[C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)[CH2:44][N:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:3][CH2:2][N:1]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCc2nc3ccccc3c3ccccc23)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1

Procedure:
Tri-tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (33.5 mg, 65.1 mop was dissolved in dry CH3CN (10 mL) and magnetically stirred under N2(g). Anhydrous K2CO3 (30.0 mg, 0.217 mmol) was added, followed by 2-chloro-N-(phenanthridin-6-ylmethyl)acetamide (Weitz et al., J. Am. Chem. Soc., 2012, 134, 16099-16102) (15.4 mg, 54.2 mmol) dissolved in 15 mL CH3CN/DMF (2:1), and the reaction mixture was heated to reflux for 27 hours under N2(g). The reaction mixture was then filtered and concentrated under reduced pressure to yield a colorless glass that was used without further purification in the next step. 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 27H), 2.70-3.21 (m, 16H), 3.37-3.42 (m, 6H), 5.41 (d, J=15 Hz, 2H), 7.66-7.87 (m, 3H), 8.02 (d, J=7.0 Hz, 1H), 8.22 8.28 (d, J=6.5 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.63 (d, J=7.5 Hz, 1H), 8.77 (d, J=7.0 Hz, 1H). HRMS (ESI): calc for [C42H62N6O7]+ ([M+H]+): m/z 763.4753. found: 763.4739.
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.O>CCOCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Solvent: O
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1.5 g of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (12 mmol) in 40 mL of ether was added 16 mL of n-BuLi (1.6M solution in hexanes, 25 mmol) at 0° C. This solution was stirred for 30 min at room temperature. 6-Methyl-6-phenylfulvene, 1.0 g,(6 mmol) in 5 mL of ether was added dropwise at -78° C. and the color of the reaction mixture turned green. The resulting solution was stirred for 7 h at -78° C. and the color of the reaction mixture turned yellow. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 1.0 g (99% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =6.0° (CHCl3, 17.4% ee.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](I)=[CH:13][C:12]=1[CH3:19]>>[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][C:12]=1[CH3:19]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2cccnc2)cc(C)c1Br

Procedure:
The title compound is prepared from pyridine-3-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.99 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13]OC(OC)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (5.0 g, 22 mmol) in MeOH (10 mL) was added 2,2-dimethoxypropane (3.4 g, 33 mmol) and 4-methylbenzene-1-sulfonic acid (2.0 mg, 0.010 mmol). The resulting solution was stirred overnight at 55° C. and allowed to cool to rt. The resulting mixture was concentrated under reduced pressure and poured into water (100 mL). The solids were collected by filtration and washed with hexanes (2×20 mL) to obtain compound 50a as a gray solid. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.54-7.51 (m, 2H), 7.35-7.28 (m, 2H), 5.18-5.16 (m, 1H), 3.793 (s, 3H), 3.51-3.49 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol (260 mg, 0.69 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively 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=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (218 mg, 58%).
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[OH-:16].[Na+]>O>[S:1]([C:5]1[S:13][C:12]2[CH:11]=[CH:10][NH:9][C:8](=[O:16])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: [OH-]
Reactant: NS(=O)(=O)c1cc2c(Cl)nccc2s1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc2c(=O)[nH]ccc2s1
Temperature: 100 °C
Yield: 66 %

Procedure:
A solution of 2-sulfamoyl-4-chlorothieno[3,2-c]pyridine (0.87 g, 3.5 mmol) in 10 N sodium hydroxide (1.8 ml) diluted with water (7 ml) was heated at 100° C. for 5-10 hours. After cooling the reaction and acidification with concentrated hydrochloric acid, the precipitated product was collected by filtration. Recrystallization from hot dimethyl sulfoxide by dilution with ethanol gives 0.53 g (66% yield) of product; m.p. 299°-301° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])[CH:3]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-1H-indazol-4-amine (available from Sinova, 100 mg, 0.47 mmol), 2-pyridinecarbonyl chloride hydrochloride (available from Apollo, 100 mg, 0.71 mmol), DIPEA (0.164 ml) in DCM (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Purification by Mass Directed Automated Preparative HPLC (Method B) gave after evaporation of solvents the title compound (38 mg) as a white solid. LCMS (Method B) Rt=0.97 mins, MH+=318.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.C(N(CC)CC)C.[NH2:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=1>C1COCC1>[NH2:7][C:5]1[S:6][C:2]([NH:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[N:3][N:4]=1
Reactant: Nc1nnc(Br)s1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nnc(NCC(O)COc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.54 g (3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amine and 0.45 ml of triethylamine are added to 0.8 g (3 mmol) of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol in 20 ml of THF and the mixture is reacted in a manner analogous to Example 51. The oil obtained is purified by column chromatography (silica gel; ammoniacal. Methanolchloroform solution (5+95)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C>[CH2:25]([O:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])[CH2:19][CH2:18]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC(O)CC1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.42 g (18.86 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)propionic acid in 20 ml of DMF was added dropwise over the course of 30 min to a suspension of 1.89 g (47.14 mmol) of 60% sodium hydride in 20 ml of DMF at 0° C. Then 2.28 g (18.86 mmol) of allyl bromide were added, and the mixture was warmed to RT and then stirred for 3 h. It was cautiously quenched with water and concentrated. The residue was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with 6M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated. The title compound obtained in this way was reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[N+]([O-])=O.[CH3:14][O-:15].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: C[O-]
Reactant: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
4.5 g (25 mmol) of 3-methoxy-2-methyl-4-nitropyridine 1-oxide are stirred at 40° C. in 75 ml of dry methanol, after addition of 4.7 ml of 30% strength sodium methylate solution, for 16 hours. The mixture is then cooled, brought to pH 7 with concentrated sulfuric acid, filtered and concentrated completely in vacuo, the oily, reddish residue is taken up in 50 ml of toluene, the mixture is filtered again to remove insoluble constituents and the filtrate is concentrated to dryness. The yellow oily residue crystallizes on an ice-bath and is finally extracted by stirring with 30 ml of petroleum ether (50/70) at 40° C. filtration and drying in a desiccator gives 5.2 g (88% of theory) of 3,4-dimethoxy-2-methyl-pyridine 1-oxide in the form of pale yellow crystals of m.p. 111°-113° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:25])[NH:9][C:10]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.Cl[C:32]1N=C(C2C=CN=CC=2)C(C2C=CC(F)=CC=2)=CN=1.ClC1C(C2C=CC=CC=2)=C(C2C=CN=CC=2)N=C(C2C=CN=CC=2)N=1.C[O-].[Na+]>CO>[CH3:32][O:25][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: O=c1[nH]c(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1
Reactant: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1
Agent: C[O-]
Agent: Clc1nc(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1

Procedure:
A mixture of 5-phenyl-2,6-bis-(4-pyridyl)-4(3H)-pyrimidinone (360 mg, 1.10 mmol) and phosphorus oxychloride (2 ml) was heated at reflux for 1.5 h. Work-up was done as described for the preparation of 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine. To a solution of the crude 4-chloro-5-phenyl-2,6-bis-(4-pyridyl)-pyrimidine (250 mg, 0.73 mmol) in methanol (5 ml) was added methanolic 0.5 N sodium methoxide (1.45 ml, 0.73 mmol) and it was heated at reflux for 1 h. After evaporation, the resultant material was partitioned between ethyl acetate and water. The organic solution was washed with water, dried and evaporated. Chromatography of the crude product on a column of silica gel (ethyl acetate) provided the title compound. MS (m/z): 341.2 (M+H)+; C21H16N4O requir. 340.4 1H-NMR (CDCl3) 8.82, 8.54, 8.40 (3m, each 2H, Pyrid.), 7.40-7.18, (m, 7H, Ph. Pyrid.), 4.15 (s, 3H, CH3O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[C:16]([CH3:15])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=Cc1ccccc1)C(=O)Nc1cccc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chloroaniline (0.98 mL, 9.3 mmol) in CH2Cl2 (25 mL) at 0° C. is added pyridine (0.78 mL, 9.5 mmol). To the resulting solution is added dropwise a solution of α-methyl cinnamic acid chloride (1.6 g, 9.3 mmol) in CH2Cl2 (8 mL). After 3 hours, the solution is concentrated. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound is obtained as a solid (2.5 g, 9.2 mmol). 1H NMR (CDCl3, 300 MHz) δ7.95 (m, 1H), 7.73 (s, 1H), 7.46 (m, 1H), 7.33 (m, 6H), 7.22 (m, 1H), 7.03 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](O)([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[N-:13]=[N+:14]=[N-:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:11])[CH2:10][N:13]=[N+:14]=[N-:15])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(C(C)(C)O)c1
Product: COc1cccc(C(C)CN=[N+]=[N-])c1
Yield: 19 %

Procedure:
Ethyl 3-methoxybenzoate (10 g, 56 mmol) was dissolved in 55 mL ether, cooled to −78° C., and treated with 55 mL 3.0 M methylmagnesium bromide in ether. The reaction was warmed to room temperature, stirred overnight, and excess reagent was quenched by addition of water and 6 M H2SO4 to the reaction at 0° C. 8.2 g (49 mmol, 89%) of 2-(3-methoxyphenyl)propan-2-ol was obtained as a colorless oil. NMR (1H, CDCl3): 7.25 (m, 1H), 7.07 (m, 2H), 6.79 (m, 1H), 3.80 (s, 3H), 1.56 (s, 6H). The alcohol (8.2 g, 49 mmol) was converted to the azide by the method reported in J. Org. Chem. 1993, 58, 5886. 1.8 g (9.4 mmol, 19%) of 2-(3-methoxyphenyl)propylazide was obtained. NMR (1H, CDCl3) 7.5-6.7 (m, 4H), 3.8 (s, 3H), 1.55 (s, 6H). The azide (1.8 g, 9.4 mmol) was reduced to the amine with catalytic 10% Pd/C, H2 (40 psi), and 5 mL conc. HCl in 75 mL ethanol. 1.5 g (9.3 mmol, 99%) of 2-(3-methoxyphenyl)propyl-2-amine was obtained as an oil. MS (Cl) m/z 166 (MH+). The amine was converted to the amide with (R,R)-2-phenylcyclopropanecarboxylic acid, then reduced to the amine using the method in example 2.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 339 mg (1.79 mmol) 1-bromomethyl-3-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CCO.O>[O:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Phenol (1.88 g, 20 mmol) was mixed with NaOH (0.80 g, 20 mmol) in EtOH (50 mL). 8-Bromooctanoic acid (2.23 g, 10 mmol) was then added to the mixture and refluxed for 12 h. After cooling to room temperature, water (100 mL) was added and the mixture was acidified with 2N HCl (pH=2). The solid was filtered and washed with water (2×50 mL), and recrystallized from hexane-ethyl acetate (5:1) to give the product as white brick-like crystals (1.79 g, 76%), mp 67-68° C.; 1H-NMR: 1.42 (m, 6H), 1.65 (m, 2H), 1.80 (m, 2H), 2.37 (t, 2H), 3.97 (t, 2H), 6.93 (m, 3H), 7.30 (t, 2H), 10.05 (bs, 1H). Anal. Calcd. for C14H20O3 : C, 71.16, H, 8.53%; Found: C, 71.09, H, 8.54%.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[S:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(N=C=S)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(OC)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-methoxyphenyl isothiocyanate (11.6 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 19 in Table 1, below (21.4 mg, 55%). 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1H), 8.67 (s, 1H), 7.47 (s, 1H), 7.30-7.21 (m, 1H), 6.80-6.68 (m, 3H), 4.32 (q, J=6.90 Hz, 2H), 4.23-3.89 (m, 8H), 3.79 (s, 3H), 1.48 (t, J=7.16 Hz, 3H) ppm.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N#N.[C:20]([NH:23][C@H:24]([C:40]([OH:42])=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(=[O:22])[CH3:21].C(N=C=NCCCN(C)C)C.[C:54]([O:58][C:59](=[O:83])[CH:60]([CH2:81][NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:74][CH2:73][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:71][CH2:70]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59](=[O:83])[CH:60]([CH:81]([C:40](=[O:42])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:23][C:20](=[O:22])[CH3:21])[NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:70][CH2:71][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:73][CH2:74]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:56])([CH3:55])[CH3:57]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydroxybenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C,63.34; H,8.61; N,7.45. C39H60N4O9 (0.25H2O) requires C,63.48; H,8.33; N,7.59%.