Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C[N+](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)([OH:12])[C:27]([F:29])([F:28])[F:26]
Reactant: COc1ccc(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of (RS)-6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (5.56 g, 15.45 mmol) in tetrahydrofuran (280 ml) was added a solution of (trifluoromethyl)trimethylsilane (3.36 g, 23.2 mmol) in tetrahydrofuran (55 ml) dropwise (15 min) at 0° C. Tetramethylammonium fluoride (0.148 g, 1.55 mmol) was added and the mixture was stirred at 0° C. for 30 min. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (13.9 ml) was added dropwise and the mixture was stirred for 45 min at r.t. The reaction mixture was poured on ice-water and extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, heptane/EtOAc 4:1) to give the title compound (4.9 g) as a white semisolid. MS (m/e)=430.2 [M+H+].
Reaction SMILES: [OH:1][CH:2]([CH2:22][OH:23])[CH:3]([NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:24][CH:25]([CH2:45]O)[CH:26](NC(C1NC2C(C=1)=CC=CC=2)=O)C1C=CC=CC=1.C(O)(=O)C1C=CC2OCOC=2C=1.C(Cl)(=O)C(Cl)=O.NC(C1C=CC=CC=1)C(O)CO>C(N(CC)CC)C>[CH:2]([O:24][CH:25]([CH3:26])[CH3:45])([CH3:22])[CH3:3].[OH:1][CH:2]([CH2:22][OH:23])[CH:3]([NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NC(c1ccccc1)C(O)CO)c1cc2ccccc2[nH]1
Agent: NC(c1ccccc1)C(O)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(NC(c1ccccc1)C(O)CO)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C

Procedure:
N-[(1RS, 2RS)-2,3-Dihydroxy-1-phenylpropyl]-3,4-methylenedioxybenzamide may be prepared in the following manner: working as in Example 8 for the preparation of N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]-2-indolecarboxamide but starting with piperonylic acid (4.6 g), oxalyl dichloride (2.6 cc), (2RS, 3RS)-3-amino-3-phenyl-1,2-propanediol (4.17 g) and triethylamine (10.5 cc), and after the precipitate is washed with distilled water and then with diisopropyl ether, N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]-3,4-methylenedioxybenzamide (6 g), m.p. 172° C., is obtained.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccsc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Under an argon atmosphere, a suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (656 mg), 3-thiopheneboronic acid (511 mg), dichloro[bis(triphenylphosphine)]palladium (70 mg) and sodium carbonate (636 mg) in 1,2-dimethoxyethane (10 mL)-water (3 mL) was stirred at 100° C. for 2 hr. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a colorless oil (yield 549 mg, 83%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:10]([O:17][C:18](=[O:33])[C@H:19]([CH:30]([CH3:32])[CH3:31])[NH:20][C:21]([O:23]C1C=CC=CC=1)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[CH2:10]([O:17][C:18](=[O:33])[C@@H:19]([NH:20][C:21]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:23])[CH:30]([CH3:31])[CH3:32])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNCc1ccccn1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)N(C)Cc1ccccn1)C(=O)OCc1ccccc1
Yield: 90.1 %

Procedure:
A solution of 80.5 g (660 mmol) N-methylpicolylamine and 196.3 g (600 mmol) of phenoxycarbonyl-L-valine benzyl ester, prepared in step 4a above, in 600 mL of 1,4-dioxane was purged with N2. The solution was then heated at reflux for four hours under a N2 atmosphere and concentrated in vacuo. The resulting residue was dissolved in ethyl ether and extracted twice with 2N HCl. The aqueous layers were combined and washed once with ethyl ether. The aqueous layer was adjusted to about pH 9 with solid sodium carbonate and extracted twice with methylene chloride. The organic layers were combined and washed twice with 0.2M phosphate buffer (pH 7.0). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, to afford 192.2 g of the title product as a light yellow oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]CC4C=CC=CC=4)=[CH:17][C:16]=3[O:29]CC3C=CC=CC=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[OH:29])[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NC1CCCCC1)N1CCC(c2ccc(O)cc2O)C1
Reaction time: 18 h
Yield: 65.8 %

Procedure:
In a 25 ml round-bottomed flask, 0.23 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is dissolved in 4 ml of methanol in the presence of 3 ml of ethyl acetate and of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.095 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is obtained. Yield=100%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:30]1[CH2:31][CH2:32][N:1]([C:2]2[CH:3]=[C:4]([C:8]3([N:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20]4)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCC(c2cccc(N3CCOCC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
1-(3-Aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl cyclohexane (cis isomer) (150 mg) was dissolved in 1 mL dry DMF under a nitrogen atmosphere. 2-Bromoethyl ether (150 mg) and potassium carbonate (150 mg) were added and the mixture was heated to 90° C. for 6 hours. The mixture was cooled to room temperature, diluted with 20 mL ethyl acetate, and transferred to a separatory funnel. The mixture was washed 5×10 mL water and 1×10 mL brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 9/1 hexanes/ethyl acetate to give 68 mg 1-(3-morpholinophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl cyclohexane (cis isomer) as a clear oil. m.p. (HCl salt)=178-180° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:23])([F:22])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[CH:11][CH:10]=1.[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:21])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([F:23])([F:22])[F:7])=[CH:10][CH:11]=3)[CH2:37][CH2:36]2)[CH:30]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-[4-(trifluoromethyl)phenyl]-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4I)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 690.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH:10]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:11][NH:12][O:13][CH3:14].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+].[ClH:33].N>C(O)C>[ClH:33].[CH2:23]([N:12]([O:13][CH3:14])[CH2:11][CH:10]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CONCC(Cc1c(F)cccc1F)c1c(C)cccc1C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CCO
Product: CON(Cc1ccccc1)CC(Cc1c(F)cccc1F)c1c(C)cccc1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.6 g (2.0 mmol) of 3-(2,6-difluorophenyl)-methoxy-2-(2,6-dimethylphenyl)-propylamine are stirred with 0.3 g (2.8 mmol) of benzaldehyde for 1 h at 60° C. Then 10 ml of ethanol and 0.3 9 of NaBH4 are added and the mixture is stirred for 30 minutes at 50° C. It is left to cool, 10 ml of 2 N hydrochloric acid are added dropwise and the ethanol is eliminated in vacuo. The residue is combined with 10 ml of conc. ammonia and extracted twice with 30 ml of ethyl acetate. The organic phase is washed with water, dried and concentrated by evaporation in vacuo. The residue is taken up in ether and the hydrochloride is precipitated with ethereal hydrochloric acid. Yield: 0.7 g (81%), melting point: 179° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:17]=1[CH2:18][CH2:19][C:20]([OH:22])=O)=[O:15])=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:17]=1[CH2:18][CH2:19][C:20]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.00 g (0.015 mol) of 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamic acid and 2.57 g (0.016 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1.5 hours in 60 ml of tetrahydrofuran and 2.22 g (0.016 mol) of ethyl glycinate hydrochloride and 2.2 ml (0.016 mol) of triethylamine are added thereto. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatoqraphy on silica gel with ethyl acetate-ethanol (9:1) and crystallization from methanolether gives ethyl N-[2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamoyl]glycinate as white crystals with melting point 94-96°.
Reaction SMILES: CN[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[NH:20])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.C1C2[N:29]([CH2:30]C=C(C3C4C(=CC=C(N)C=4)NC=3)C2)[CH2:28]C1.I.CSC(C1SC=CC=1)=N>C(O)C>[CH2:3]1[CH:4]2[N:29]([CH2:30][CH:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[NH:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:5]2)[CH2:28][CH2:8]1
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Reactant: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Agent: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1)c1cccs1
Reaction time: 24 h
Yield: 79 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2 20 m L). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15); ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:19])[CH2:3]2
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1CN2CCC1CC2
Product: O=C(Nc1ccc(Cl)cc1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and 4-chlorophenyl isocyanate (0.768 g, 5 mmol). The product was purified as the 1:1 maleate (1.23 g), mp 182°-183° C. (dec).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>CC(C)=O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:16])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 g (30 mmol) of morpholine and 4.2 g (30 mmol) of potassium carbonate are suspended in 120 ml of acetone. 5.3 g (20 mmol) of N-bromoacetyl-4-nitro-aniline, dissolved in 80 ml of acetone, are added dropwise over a period of 20 minutes and then stirred for 2 hours at ambient temperature. The precipitate is filtered off and the solvent is eliminated in vacuo. The residue is suspended with water. The precipitate is suction filtered and dried in a drying cupboard.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15]([NH2:20])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O>C(#N)C.CN(C1C=CN=CC=1)C>[C:32]([O:31][C:29]([N:20]([C:15]1[C:16]2[C:11](=[CH:10][C:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:19])[CH:17]=2)[CH:12]=[CH:13][N:14]=1)[C:29](=[O:28])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.2 %

Procedure:
To a solution of Intermediate 4A (1.73 g, 3.78 mmol) in acetonitrile (20 mL) was added BOC2O (1.229 mL, 5.29 mmol) followed by TEA (0.527 mL, 3.78 mmol) and DMAP (0.092 g, 0.756 mmol), then the suspension was stirred at rt for 1 h. Solvent was removed under vacuum and the residue purified on Isco (120 g) eluting with 0 to 75% EtOAc/hexanes to give Intermediate 4B (2.185 g, 3.92 mmol, 104% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.38 (s, 18H) 4.54 (s, 4H) 7.04 (d, J=8.53 Hz, 1H) 7.28-7.40 (m, 11H) 7.53 (d, J=14.05 Hz, 1H) 8.25 (d, J=5.77 Hz, 1H); MS (ESI) m/z: 558.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[N:15][N:14]=2)=[CH:9][CH:8]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17][C:16]([CH2:18][NH2:19])=[N:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1

Procedure:
A solution of tert-butyl ((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate, dioxane (16 mL), and 4N HCl in dioxane (13 ml) was stirred at room temperature for 4 h. The resulting mixture was concentrated in vacuo to yield (5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methanamine, which was in the next step used directly without further purification. MS (ES+) 316 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([CH:36]=[O:37])[N:35]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:39].[Na+].P([O-])(O)(O)=O.[Na+]>CC(=CC)C.C(#N)C.C(O)(C)(C)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:15][C:16]3[CH:17]=[C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([C:36]([OH:39])=[O:37])[N:35]=5)[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH2:22][CH2:23]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(C=O)c[nH]5)c4)cc3C2)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(C(=O)O)c[nH]5)c4)cc3C2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of N-(3-tert-butylphenyl)-7-{[2-(4-formyl-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (570 mg, 1.2 mmol) in 2-methyl-2-butene (3 mL), acetonitrile (6 mL) and tert-butyl alcohol (6 mL) was cooled to 0° C. To this cold reaction mixture was added a solution of sodium chlorite (646 mg, 5.71 mmol) and sodium dihydrogenphosphate (680 mg, 5.6 mmol) in water (3 mL). The yellow solution was allowed to stir at 0° C. overnight. The reaction was quenched by the addition of brine (3 mL) and extracted with EtOAc (15 mL×3). The combined organic solutions were washed with brine and dried over Na2SO4, filtered and concentrated to give 2-{4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyridin-2-yl}-1H-imidazole-4carboxylic acid (I-155), which was used without further purification. LCMS: (FA) ES+ 511.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(Br)c1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(Br)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a mixture of 2-bromo-6-methoxybenzoic acid (40 g, 0.176 mol) in DMF (300 mL) was added K2CO3 (24.8 g, 0.176 mol) and CH3I (37 g, 0.264 mol). The mixture was stirred at RT overnight. The reaction was quenched with 1M HCl aq and the mixture was extracted with EtOAc (3×300 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (41 g, 99%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CSc1nccc(O)n1
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)CSc1nccc(Cl)n1

Procedure:
A stirred mixture of 32.1 g of (4-hydroxy-2-pyrimidinylthio)acetic acid, ethyl ester and 22.4 g of N,N-diethylaniline in 400 ml. of phosphorus oxychloride were heated under reflux for 5 hr. The phosphorus oxychloride was removed in a rotary evaporator in vacuo. The residue was poured onto ice and the mixture was extracted with 1 liter of ether. The ether solution was dried over MgSO4 and then filtered. The filtrate was taken to dryness in a rotary evaporator yielding 22.9 g of (4-chloro-2-pyrimidinylthio)acetic acid, ethyl ester (an oil). This material was used directly in the next step without purification.